Compounds comprising a spiro-ring and methods of use

ABSTRACT

The present invention provides novel compounds useful in modulating the protein tyrosine kinase activity, and in modulating inter—and/or intra—cellular signaling. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application No.61/105,414, filed Oct. 14, 2008, the content of which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

Provided herein are novel compounds that are useful in the treatment ofhyperproliferative diseases, such as cancers, in mammals. In particular,the invention relates to compounds that inhibit the protein tyrosinekinase activity, resulting in the inhibition of inter- and/orintra-cellular signaling. Provided also herein are methods of using suchcompounds in the treatment of hyperproliferative diseases in mammals,especially humans, and pharmaceutical compositions containing suchcompounds.

BACKGROUND OF THE INVENTION

Protein kinases represent a large family of proteins, which play apivotal role in the regulation of a wide variety of cellular processes,maintaining control over cellular function. Protein tyrosine kinases maybe classified as growth factor receptor (e.g. VEGFR, EGFR, PDGFR, FGFRand erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases. Thereceptor type tyrosine kinases make up about 20 different subfamilies.The non-receptor type tyrosine kinases make up numerous subfamilies.Receptor tyrosine kinases are large enzymes that span the cell membraneand possess an extracellular binding domain for growth factors, atransmembrane domain, and an intracellular portion that functions as akinase to phosphorylate a specific tyrosine residue in proteins andhence to influence cell proliferation. Aberrant or inappropriate proteinkinase activity can contribute to the rise of disease states associatedwith such aberrant kinase activity.

A partial list of such kinases include abl, AATK, ALK, Aid, axl, bmx,bcr-abl, Blk, Brk, Btk, csk, c-kit, c-Met, c-src, c-fins, CDK1, CDK2,CDK3, CDK4, CDKS, CDK6, CDK7, CDK8, CDK9, CDK10, CRaf1, CSF1R, CSK,DDR1, DDR2, EPHA, EPHB, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FER,FGFR1, FGFR2, FGFR3, FGFR4, FGFRS, Fgr, flt-1, Fps, Frk, Fyn, GSG2, GSK,Hck, ILK, INSRR, IRAK4, ITK, IGF-1R, INS-R, Jak, KSR1, KDR, LMTK2,LMTK3, LTK, Lck, Lyn, MATK, MERTK, MLTK, MST1R, MUSK, NPR1, NTRK, MEK,PLK4, PTK, p38, PDGFR, PIK, PKC, PYK2, RET, ROR1, ROR2, RYK, ros, Ron,SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TNK1, TNK2, TNNI3K, TXK,TYK2, TYRO3, tie, tie2, TRK, Yes, and Zap70. Inhibition of such kinaseshas become an important therapeutic target. Certain diseases are knownto be associated with deregulated angiogenesis, for example, ocularneovascularisation, such as retinopathies (including diabeticretinopathy); age-related macular degeneration; psoriasis;hemangioblastoma; hemangioma; arteriosclerosis; inflammatory diseases,such as a rheumatoid or rheumatic inflammatory disease, especiallyarthritis (including rheumatoid arthritis); or other chronicinflammatory disorders, such as chronic asthma; arterial orpost-transplantational atherosclerosis; endometriosis; and neoplasticdiseases, for example so-called solid tumors and liquid tumors (such asleukemias).

Angiogenesis is an important component of certain normal physiologicalprocesses such as embryogenesis and wound healing, but aberrantangiogenesis contributes to some pathological disorders and inparticular to tumor growth. VEGF-A (vascular endothelial growth factorA) is a key factor promoting neovascularization (angiogenesis) oftumors. VEGF induces endothelial cell proliferation and migration bysignaling through two high affinity receptors, the fms-like tyrosinekinase receptor, flt-1, and the kinase insert domain-containingreceptor, KDR. These signaling responses are critically dependent uponreceptor dimerization and activation of intrinsic receptor tyrosinekinase (RTK) activity. The binding of VEGF as a disulfide-linkedhomodimer stimulates receptor dimerization and activation of the RTKdomain. The kinase activity autophosphorylates cytoplasmic receptortyrosine residues, which then serve as binding sites for moleculesinvolved in the propagation of a signaling cascade.

Disruption of VEGF receptor signaling is a highly attractive therapeutictarget in cancer, as angiogenesis is a prerequisite for all solid tumorgrowth, and that the mature endothelium remains relatively quiescent(with the exception of the female reproductive system and woundhealing). A number of experiment approaches to inhibiting VEGF signalinghave been examined, including use of neutralizing antibodies receptorantagonists, small molecule antagonists, antisense constructs anddominant-negative strategies (“Molecular basis for sunitinib efficacyand future clinical development.” Nature Review Drug Discovery, 2007, 6,734; Angiogenesis: “an organizing principle for drug discovery?” NatureReview Drug Discovery, 2007, 6, 273).

Hepatocyte growth factor (HGF), also known as scatter factor, is amultifunctional growth factor that enhances transformation and tumordevelopment by inducing mitogenesis and cell motility. In order toproduce cellular effects, HGF must bind to its receptor, c-Met, areceptor tyrosine kinase. c-Met is overexpressed in a significantpercentage of various types of human cancers and is often amplifiedduring the transition between primary tumors and metastasis. c-Met isalso implicated in atherosclerosis and lung fibrosis (“Molecular cancertherapy: can our expectation be MET.” Euro. J. Cancer, 2008, 44,641-651). Invasive growth of certain cancer cells is drasticallyenhanced by tumor-stromal interactions involving the HGF/c-Met (HGFreceptor) pathway. Binding of HGF to c-Met leads to receptorphosphorylation and activation of Ras/mitogen-activated protein kinase(MAPK) signaling pathway, thereby enhancing malignant behaviors ofcancer cells. Moreover, stimulation of the HGF/c-Met pathway itself canlead to the induction of VEGF expression, itself contributing directlyto angiogenic activity (“From Tpr-Met to Met, tumorigenesis and tubes.”Oncogene. 2007, 26, 1276; “Targeting the c-Met Signaling Pathway inCancer.” Clin. Cancer Res. 2006, 12, 3657; “Drug development of METinhibitors: targeting oncogene addiction and expedience.” Nature ReviewDrug Discovery, 2008, 7, 504).

Insulin-like growth factor 1 receptor (IGF1R) is an integral membranetyrosine kinase receptor that binds insulin-like growth factor (IGF)with high affinity. IGF1R plays a critical role in transformation eventsand human cancer. It is highly over-expressed in most malignant tissueswhere it functions as an anti-apototic agent by enhancing cell survivalthrough the PI3K pathway, and also the p53 pathway. IGF1R has beenlinked to various disease states, such as breast and ovarian cancer,metastatic uveal melanoma, macular degeneration, and intrauterine growthretardation and poor postnatal growth, among others (“IGF1R signalingand its inhibition.” Endocrine-Related Cancer, 2006, 13, S33-S43; “Thenew kid on the block(ade) of the IGF-1 receptor.” Cancer Cell, 2004, 5,201.).

Anti-tumor approaches that target VEGF/VEGFR, HGF/c-Met and/or IGF/IGF1Rsignaling may circumvent the ability of tumor cells to overcome VEGFR,HGFR or IGF1R inhibition alone and may represent improved cancertherapeutics. Here we describe small molecules that are potentinhibitors of protein tyrosine kinase activity, such as that of, forexample, the VEGF receptor KDR, the HGF receptor c-Met, and/or the IGFreceptor IGF1R, among others.

SUMMARY OF THE INVENTION

Provided herein are new compounds and methods for treating cellproliferative diseases. The compounds disclosed herein may be inhibitorsof protein tyrosine kinase activity. In some embodiments, the compoundsdisclosed herein are multiple function inhibitors, capable ofinhibiting, for example, VEGF, HGF and/or IGF receptor signaling.Accordingly, provided herein are new inhibitors of protein tyrosinekinase receptor signaling, such as for example, VEGF receptor signaling,HGF receptor signaling, and/or IGF receptor signaling, including theVEGF receptor KDR, the HGF receptor c-Met, and/or IGF1R.

Specifically, it has been found that compounds disclosed herein, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of receptor tyrosine kinases, especially c-Met, KDR and/orIGF1R. In one aspect, provided herein are compounds having Formula (I)as shown below:

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, ahydrate, a solvate, a metabolite, a pharmaceutically acceptable salt ora prodrug thereof, wherein each of R³, U₁, X₁, Q₁ and Q₂ is as definedherein.

In another aspect, provided herein are compounds having Formula (IV) asshown below:

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, ahydrate, a solvate, a metabolite, a pharmaceutically acceptable salt ora prodrug thereof, wherein each of R³, U₁, V₁, V₂, V₃, V₄, X₁, X₂, Z,and Q₂ is as defined herein.

In another aspect, provided herein are compounds having Formula (V) asshown below:

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, ahydrate, a solvate, a metabolite, a pharmaceutically acceptable salt ora prodrug thereof, wherein each of R³, U₁, V, X₁, X₂, X₃, Z₁, Z₂ and Q₂is as defined herein.

In certain embodiments, Q₁ of formula (I) has Formula (IIa) or (IIb):

wherein each of V, V₁, V₂, V₃, V₄, X₂, X₃, Z, Z₁ and Z₂ is as definedherein.

In other embodiments, formula (IIa) is

wherein each of R^(3a), R⁵, R^(5a), Z is as defined herein.

In other embodiments, formula (IIb) is

wherein Ar is substituted or unsubstituted aryl or heteroaryl; and s is0 or 1.

In some embodiments, Q₂ of formula (I), (IV) or (V) has Formula (III):

wherein each of R¹, R², W₁, W₂, W₃, W₄ and U₂ is as defined herein.

In certain embodiments, Q₂ of formula (I), (IV) or (V) is

wherein each of R¹, R² and R⁵ is as defined herein.

In some embodiments, each R¹ disclosed herein is independentlyR^(5a)R⁵N—, —OC(═O)NR⁵R^(5a), —OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a),—NR⁵C(═O)—R^(5a), R⁵R^(5a)N—O₂S—, R⁵O₂S—, R⁵O₂SR^(5a)N—, R⁵S(═O)-alkyl,R⁵R^(5a)N—C(═O)—C₁₋₆ alkyl, R⁵S(═O)-alkoxy, R⁵R^(5a)N—C(═O)-alkoxy,hydroxy-substituted aminoalkoxy, amino-substituted haloalkoxy,hydroxy-substituted haloalkoxy, heterocyclyl(aminoalkoxy),heteroaryl(hydroxyalkoxy), hydroxy-substituted cyclopropylalkoxy,R⁵S(═O)₂O-substituted cyclopropylalkoxy, fused bicyclyl, fusedheterobicyclyl, fused bicyclyl aliphatic, fused heterobicyclylaliphatic, fused bicycloxy, fused heterobicycloxy, fused bicyclylamino,fused heterobicyclylamino, fused bicycloxoalkoxy, fusedheterobicycloxoalkoxy, fused bicyclyl aminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl-C(═O)—, fused bicyclyl-C(═O)O—, fusedheterobicyclyl-C(═O)—, fused heterobicyclyl-C(═O)O—, fusedbicyclylamino-C(═O)—, fused heterobicyclylamino-C(═O)—, fusedbicyclyl-C(═O)NR⁵—, fused heterobicyclyl-C(═O)NR⁵—, spiro bicyclyl,spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclylaliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino,spiro heterobicyclylamino, spiro bicycloxoalkoxy, spiroheterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spiro bicyclyl —C(═O)—, spirobicyclyl-C(═O)O—, spiro heterobicyclyl-C(═O)—, spiroheterobicyclyl-C(═O)O—, spiro bicyclylamino-C(═O)—, spiroheterobicyclylamino-C(═O)—, spiro bicyclyl-C(═O)NR⁵—, or spiroheterobicyclyl-C(═O)NR⁵—.

In other embodiments, each R¹ disclosed herein is independentlyR^(5a)R⁵N—, —OC(═O)NR⁵R^(5a), —OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a),—NR⁵C(═O)—R^(5a), R⁵R^(5a)N—O₂S—, R⁵O₂S—, R⁵O₂SR^(5a)N—, R⁵S(═O)-alkyl,R⁵R^(5a)N—C(═O)—C₁₋₆ alkyl, R⁵S(═O)-alkoxy, R⁵R^(5a)N—C(═O)-alkoxy,hydroxy-substituted C₁₋₆ aminoalkoxy, amino-substituted C₁₋₆haloalkoxy,hydroxy-substituted C₁₋₆ haloalkoxy, C₄₋₁₀heterocyclylamino C₁₋₆alkoxy,C₁₋₁₀ heteroaryl(hydroxyalkoxy), hydroxy-substituted cyclopropylC₁₋₆alkoxy, R⁵S(═O)₂O-substituted cyclopropyl C₁₋₆alkoxy, C₅₋₁₂ fusedbicyclyl, C₅₋₁₂ fused heterobicyclyl, C₅₋₁₂ fused bicyclyl aliphatic,C₅₋₁₂ fused heterobicyclyl aliphatic, C₅₋₁₂ fused bicycloxy, C₅₋₁₂ fusedheterobicycloxy, C₅₋₁₂ fused bicyclylamino, C₅₋₁₂ fusedheterobicyclylamino, C₅₋₁₂ fused bicycloxoalkoxy, C₅₋₁₂ fusedheterobicycloxo C₁₋₆ alkoxy, C₅₋₁₂ fused bicyclyl-C(═O)—, C₅₋₁₂ fusedbicyclyl-C(═O)O—, C₅₋₁₂ fused heterobicyclyl-C(═O)—, C₅₋₁₂ fusedheterobicyclyl-C(═O)O—, C₅₋₁₂ fused bicyclylamino-C(═O)—, C₅₋₁₂ fusedheterobicyclylamino-C(═O)—, C₅₋₁₂ fused bicyclyl-C(═O)NR⁵—, C₅₋₁₂ fusedheterobicyclyl-C(═O)NR⁵—, C₅₋₁₂ spiro bicyclyl, C₅₋₁₂ spiroheterobicyclyl, C₅₋₁₂ spiro bicyclyl C₁₋₆ aliphatic, C₅₋₁₂ spiroheterobicyclyl C₁₋₆ aliphatic, C₅₋₁₂ spiro heterobicycloxo C₁₋₆ alkoxy,C₅₋₁₂ spiro heterobicyclylamino C₁₋₆ alkoxy, C₅₋₁₂ spiro bicyclyl—C(═O)—, C₅₋₁₂ spiro bicyclyl-C(═O)O—, C₅₋₁₂ spiroheterobicyclyl-C(═O)—, C₅₋₁₂ spiro heterobicyclyl-C(═O)O—, C₅₋₁₂ spirobicyclylamino-C(═O)—, C₅₋₁₂ spiro heterobicyclylamino-C(═O)—, C₅₋₁₂spiro bicyclyl-C(═O)NR⁵—, or C₅₋₁₂ spiro heterobicyclyl-C(═O)NR⁵—.

In further embodiments, each R¹ disclosed herein is independently hasone of the following structures:

wherein each of X₄ and X₄′ is independently (CR⁴R^(4a))_(m), NR⁵, O, S,S═O or SO₂; each of m and n is independently 0, 1 or 2; and t is 1, 2 or3.

In certain embodiments, each R² disclosed herein is independently H,halo, cyano, hydroxyl, R^(5a)R⁵N—, —C(═O)NR⁵R^(5a), —OC(═O)NR⁵R^(5a),—OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a), —NR⁵C(═O)OR^(5a), —NR⁵C(═O)—R^(5a),R⁵R^(5a)N—O₂S—, R⁵O₂S—, R⁵O₂SR^(5a)N—, R^(5a)R⁵N-alkyl, R⁵S(═O)-alkyl,R⁵R^(5a)N—C(═O)-alkyl, R^(5a)R⁵N-alkoxy, R⁵S(═O)-alkoxy,R⁵R^(5a)N—C(═O)-alkoxy, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy,hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substitutedhaloalkoxy, alkylamino haloalkoxy, hydroxy-substituted haloalkoxy,alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy,carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy),carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy,heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy,cycloalkyloxy, (heterocyclo)hydroxyalkoxy, azidoalkoxy, fused bicyclyl,fused heterobicyclyl, fused bicyclyl aliphatic, fused heterobicyclylaliphatic, fused bicycloxy, fused heterobicycloxy, fused bicyclylamino,fused heterobicyclylamino, fused bicycloxoalkoxy, fusedheterobicycloxoalkoxy, fused bicyclyl aminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl-C(═O)—, fused bicyclyl-C(═O)O—, fusedheterobicyclyl-C(═O)—, fused heterobicyclyl-C(═O)O—, fusedbicyclylamino-C(═O)—, fused heterobicyclylamino-C(═O)—, fusedbicyclyl-C(═O)NR⁵—, fused heterobicyclyl-C(═O)NR⁵—, spiro bicyclyl,spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclylaliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino,spiro heterobicyclylamino, spiro bicycloxoalkoxy, spiroheterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spiro bicyclyl —C(═O)—, spirobicyclyl-C(═O)O—, spiro heterobicyclyl-C(═O)—, spiroheterobicyclyl-C(═O)O—, spiro bicyclylamino-C(═O)—, Spiroheterobicyclylamino-C(═O)—, spiro bicyclyl-C(═O)NR⁵—, or spiroheterobicyclyl-C(═O)NR⁵—, aryl, heteroaryl, arylaliphatic orheteroarylaliphatic, with the proviso that when alkoxy or alkylamino issubstituted, each of alkoxy or alkylamino is independently substitutedwith one or more hydroxy groups, amino groups or substituted aminogroups.

In other embodiments, each R² disclosed herein is independently H, halo,cyano(CN), R^(5a)R⁵N—C₁₋₆ alkoxy, optionally substituted C₁₋₆ alkoxy,C₁₋₆ hydroxyalkoxy, C₁₋₆ aminoalkoxy, C₁₋₆ hydroxy-substitutedaminoalkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino C₁₋₆ alkoxy, C₁₋₆ alkoxyC₁₋₆ alkoxy, C₄₋₁₀ heterocyclyloxy C₁₋₆ alkoxy, C₅₋₁₂ fused bicyclyl,C₅₋₁₂ fused bicyclyl C₁₋₆ aliphatic, C₅₋₁₂ fused heterobicyclyl C₁₋₆aliphatic, C₅₋₁₂ fused bicycloxy, C₅₋₁₂ fused bicyclylamino, C₅₋₁₂ fusedbicycloxo C₁₋₆ alkoxy, C₅₋₁₂ fused bicyclylamino C₁₋₆ alkoxy, C₅₋₁₂fused bicyclyl-C(═O)—, C₅₋₁₂ fused bicyclyl-C(═O)O—, C₅₋₁₂ fusedheterobicyclyl-C(═O)—, C₅₋₁₂ fused heterobicyclyl-C(═O)O—, C₅₋₁₂ fusedbicyclylamino-C(═O)—, C₅₋₁₂ fused heterobicyclylamino-C(═O)—, C₅₋₁₂fused bicyclyl-C(═O)NR⁵—, C₅₋₁₂ fused heterobicyclyl-C(═O)NR⁵—, C₅₋₁₂spiro bicyclyl, C₅₋₁₂ spiro bicycloxy, C₅₋₁₂ spiro bicyclylamino, C₅₋₁₂spiro bicycloxo C₁₋₆ alkoxy, C₅₋₁₂ spiro bicyclylamino C₁₋₆ alkoxy,C₅₋₁₂ fused heterobicyclyl, C₅₋₁₂ fused heterobicycloxy, C₅₋₁₂ fusedheterobicyclylamino, C₅₋₁₂ fused heterobicycloxo C₁₋₆ alkoxy, C₅₋₁₂fused heterobicyclylamino C₁₋₆ alkoxy, C₅₋₁₂ spiro bicyclyl, C₅₋₁₂ spiroheterobicyclyl, C₅₋₁₂ spiro bicyclyl C₁₋₆ aliphatic, C₅₋₁₂ spiroheterobicyclyl C₁₋₆ aliphatic, C₅₋₁₂ spiro heterobicycloxo C₁₋₆ alkoxy,C₅₋₁₂ spiro heterobicyclylamino C₁₋₆ alkoxy, C₅₋₁₂ spiro bicyclyl—C(═O)—, C₅₋₁₂ spiro bicyclyl-C(═O)O—, C₅₋₁₂ spiroheterobicyclyl-C(═O)—, C₅₋₁₂ spiro heterobicyclyl-C(═O)O—, C₅₋₁₂ spirobicyclylamino-C(═O)—, C₅₋₁₂ spiro heterobicyclylamino-C(═O)—, C₅₋₁₂spiro bicyclyl-C(═O)NR⁵—, or C₅₋₁₂ spiro heterobicyclyl-C(═O)NR⁵—, C₆₋₁₀aryl, C₁₋₁₀ heteroaryl, C₆₋₁₀ aryl C₁₋₆ aliphatic or C₁₋₁₀ heteroarylC₁₋₆ aliphatic.

In some embodiments, each of R³ and R^(3a) disclosed herein isindependently H, F, Cl, Br, I, —CN, hydroxyl, R^(5a)R⁵N—,R^(5a)R⁵N-aliphatic, hydroxyaliphatic, aliphatic, alkoxy,alkoxyaliphatic, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl,cycloalkoxy aliphatic, heterocycloxy aliphatic, cycloalkylalkoxy,heterocyclylalkoxy, aryloxyalkyl, heteroaryloxy aliphatic,arylaliphatic, heteroaryl aliphatic, aryl, or heteroaryl. In otherembodiments, each of R³ and R^(3a) disclosed herein is independently H,F, Cl, Br, —CN, R^(5a)R⁵N—C₁₋₃ aliphatic, C₁₋₃ aliphatic, C₁₋₃ alkoxyC₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkyl, cycloalkoxy C₁₋₃ aliphatic, orheterocycloxy C₁₋₃ aliphatic.

In certain embodiments, each of U₁ and U₂ disclosed herein isindependently CR⁴ or N.

In some embodiments, each V disclosed herein is independently NR⁵R^(5a),OR⁵, aliphatic, cycloalkyl, heterocyclyl, aryl, heteroaryl,arylaliphatic, or heteroarylaliphatic. In other embodiments, each V₁disclosed herein is O or NR⁵. In further embodiments, each of V₂, V₃ andV₄ disclosed herein is independently CR⁴R^(4a), NR⁵, CR⁴ or N, with theproviso that only one of V₂, V₃, and V₄ is NR⁵ or N, or V₂ and V₃ or V₃and V₄ combine to become CR⁴R^(4a), NR⁵, O, CR⁴ or N, with the provisothat the resulted structure is stable.

In certain embodiments, each of W₁, W₂, W₃ and W₄ disclosed herein isindependently CR⁴R^(4a), NR⁵, CR⁴ or N₁ or W₁ and W₂ or W₃ and W₄combine to become CR⁴R^(4a), NR⁵, O or S.

In some embodiments, each X₁ disclosed herein is independently(CR⁴R^(4a))_(m), NR⁵, O, S, S═O or SO₂, where m is 0, 1 or 2. In otherembodiments, each X₁ disclosed herein is independently O or NR⁵. Infurther embodiments, each of X₂ and X₃ disclosed herein is independentlyO, S or NR⁵.

In certain embodiments, each Z disclosed herein is independently—NR⁵C(═O)(CR⁴R^(4a))_(p)—, —NR⁵C(═S)(CR⁴R^(4a))_(p)—,—NR^(5a)(CR⁴R^(4a))_(p)—, —NR⁵(CR⁴R^(4a))_(p)C(═O)—,—NR⁵(CR⁴R^(4a))_(p)C(═S)—, —NR⁵S(═O)_(t), —NR⁵S(═O)_(r)(CR⁴R^(4a))_(p)—,—C(═O)NR⁵(CR⁴R^(4a))_(p)— or —NR⁵(CR⁴R^(4a))_(p)S(═O)_(c), where p is 0,1, 2 or 3; and r is 1 or 2.

In some embodiments, Z of formula (IIa) is —NHC(═O)—; Z₁ of formula(IIb) is NH; and the substructure defined by X₁, U₁ and R³ of Formula Iis:

In some embodiments, each of R⁴ and R^(4a) disclosed herein isindependently H, F, Cl, Br, I, —CN, hydroxyl, —NR^(5a)R⁵, alkoxy,cycloalkoxy, heterocycloalkoxy, aliphatic, haloaliphatic,hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic,alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic,cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic,cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl,with the proviso that where R⁴ and R^(4a) are bonded to the same carbonatom, R⁴ and R^(4a), together with the carbon atom they are attached to,optionally form a substituted or unsubstituted 3-8 membered carbocyclicor heterocyclic ring.

In certain embodiments, each of R⁵ and R^(5a) is independently H,R⁶R^(6a)NC(═O)—, R⁶OC(═O)—, R⁶C(═O)—, R⁶R^(6a)NS(═O)—, R⁶OS(═O)—,R⁶S(═O)—, R⁶R^(6a)NSO₂—, R⁶OSO₂—, R⁶SO₂—, aliphatic, haloaliphatic,hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic,alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic,cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic,cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl,with the proviso that where R⁵ and R^(5a) are bonded to the samenitrogen atom, R⁵ and R^(5a), together with the nitrogen atom they areattached to, optionally form a substituted or unsubstituted 3-8 memberedring, including spiro and fused bicyclic rings.

In certain embodiments, each of R⁶ and R^(6a) is independently H,aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic,alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic,heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic,heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic,heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl,heterocyclyl, carbocyclyl.

In some embodiments, each of R^(5a)R⁵N—, —C(═O)NR⁵R^(5a),—OC(═O)NR⁵R^(5a), —OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a), —NR⁵C(═O)OR^(5a),—NR⁵C(═O)—R^(5a), R⁵R^(5a)N—O₂S—, R⁵O₂S—, R⁵O₂SR^(5a)N—, OR⁵, NR⁵,CR⁴R^(4a), CR⁴, (CR⁴R^(4a))_(m), —NR⁵C(O)—(CR⁴R^(4a))_(p)—,—NR⁵C(═S)—(CR⁴R^(4a))_(p)—, —NR^(5a)—(CR⁴R^(4a))_(p)—,—NR⁵—(CR⁴R^(4a))_(p)C(═O)—, —NR⁵—(CR⁴R^(4a))_(p)C(═S)—, —NR⁵S(O)_(r)—,—NR⁵S(═O)(CR⁴R^(4a))_(p)—, —C(═O)NR⁵—(CR⁴R^(4a))_(p)— or—NR⁵—(CR⁴R^(4a))_(p)—S(═O)_(r)—, R^(5a)R⁵N-alkyl, R⁵(S(═O)_(r)-alkyl,R⁵R^(5a)N—C(═O)—C₁₋₆ alkyl, R^(5a)R⁵N—C₁₋₆ alkoxy, R⁵S(═O)_(r)-alkoxy,R⁵R^(5a)N—C(═O)-alkoxy, R⁶R^(6a)NC(═O)—, R⁶OC(═O)—, R⁶C(═O)—,R⁶R^(6a)NS(═O)—, R⁶OS(═O)—, R⁶S(═O)—, R⁶R^(6a)NSO₂—, R⁶SO₂—, R⁶SO₂—,aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy, hydroxy-substitutedaminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylaminohaloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy,alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy,heterocyclyl(hydroxyalkoxy), carbocyclyl(hydroxyalkoxy),aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy,carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy,(heterocyclo)hydroxyalkoxy, azidoalkoxy, fused bicyclyl, fusedheterobicyclyl, fused bicyclyl aliphatic, fused heterobicyclylaliphatic, fused bicycloxy, fused heterobicycloxy, fused bicyclylamino,fused heterobicyclylamino, fused bicycloxoalkoxy, fusedheterobicycloxoalkoxy, fused bicyclyl aminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl-C(═O)—, fused bicyclyl-C(═O)O—, fusedheterobicyclyl-C(═O)—, fused heterobicyclyl-C(═O)O—, fusedbicyclylamino-C(═O)—, fused heterobicyclylamino-C(═O)—, fusedbicyclyl-C(═O)NR⁵—, fused heterobicyclyl-C(═O)NR⁵—, spiro bicyclyl,spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclylaliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino,spiro heterobicyclylamino, spiro bicycloxoalkoxy, spiroheterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spiro bicyclyl —C(═O)—, spirobicyclyl-C(═O)O—, spiro heterobicyclyl-C(═O)—, spiroheterobicyclyl-C(═O)O—, spiro bicyclylamino-C(═O)—, spiroheterobicyclylamino-C(═O)—, spiro bicyclyl-C(═O)NR⁵—, or spiroheterobicyclyl-C(═O)NR⁵—, aryl, heteroaryl, arylaliphatic andheteroarylaliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic,alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic,heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic,heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic,heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, heterocyclyl andcarbocyclyl disclosed herein is independently substituted orunsubstituted.

In another aspect, provided herein are pharmaceutical compositionscomprising a compound disclosed herein, or a stereoisomer, geometricisomer, tautomer, solvate, metabolite, pharmaceutically acceptable saltor prodrug thereof, and an optional pharmaceutically acceptable carrier,excipient, diluent, adjuvant, vehicle or a combination thereof. Incertain embodiments, the compound is an inhibitor of protein tyrosinekinase. In other embodiments, the compound is an inhibitor of VEGFreceptor signaling, HGF receptor signaling and/or IGF receptorsignaling.

In some embodiments, the composition disclosed herein further comprisesan additional therapeutic agent. In other embodiments, the therapeuticagent is a chemotherapeutic agent, an anti-proliferative agent, an agentfor treating atherosclerosis, an agent for treating lung fibrosis, andcombinations thereof.

In further embodiments, the therapeutic agent is adriamycin, rapamycin,temsirolimus, everolimus, ixabepilone, gemcitabine, cyclophosphamide,dexamethasone, etoposide, fluorouracil, imatinib mesylate, dasatinib,nilotinib, erlotinib, lapatinib, iressa, sorafenib, sunitinib, aninterferon, carboplatin, topotecan, taxol, vinblastine, vincristine,temozolomide, tositumomab (Bexxar), trabedectin, Avastin (bevacizumab),Herceptin (trastuzumab), Erbitux (cetuximab), Vectibix (panitumumab) ora combination thereof.

In another aspect, provided herein are methods for preventing, managing,treating or lessening the severity of a proliferative disorder in apatient infected with the proliferative disorder, which comprisesadministrating a pharmaceutically effective amount of a compounddisclosed herein to the patient.

In another aspect, provided herein are methods for preventing, managing,treating or lessening the severity of a proliferative disorder in apatient infected with the proliferative disorder, which comprisesadministrating a pharmaceutically effective amount of a pharmaceuticalcomposition disclosed herein to the patient.

In another aspect, provided herein is use of the compound disclosedherein in the manufacture of a medicament for preventing, managing,treating or lessening the severity of a proliferative disorder in apatient.

In another aspect, provided herein is use of the pharmaceuticalcomposition disclosed herein in the manufacture of a medicament forpreventing, managing, treating or lessening the severity of aproliferative disorder in a patient.

In some embodiments, the proliferative disorder is metastatic cancer. Inother embodiments, the proliferative disorder is colon cancer, gastricadenocarcinoma, bladder cancer, breast cancer, kidney cancer, livercancer, lung cancer, thyroid cancer, cancer of the head and neck,prostate cancer, pancreatic cancer, cancer of the CNS, glioblastoma, ora myeloproliferative disorder. In further embodiments, the proliferativedisorder is atherosclerosis or lung fibrosis.

In another aspect, provided herein is a method of inhibiting ormodulating protein kinase activity in a biological sample comprisingcontacting a biological sample with the compound disclosed herein.

In another aspect, provided herein is a method of inhibiting ormodulating protein kinase activity in a biological sample comprisingcontacting a biological sample with the pharmaceutical compositiondisclosed herein.

In some embodiments, the protein kinases are receptor tyrosine kinases.In other embodiments, the receptor tyrosine kinases are KDR, c-Met orIGF1R.

In another aspect, provided herein is a method of inhibiting proteintyrosine kinase, the method comprises contacting the kinase with acompound disclosed herein, or with a composition disclosed herein. Inother embodiments, provided herein is a method of inhibiting VEGFreceptor signaling, HGF receptor signaling and/or IGF receptorsignaling, the method comprises contacting the receptor with a compounddisclosed herein, or with a composition disclosed herein. Inhibition ofreceptor protein kinase activity, in some embodiments, VEGF, HGF and/orIGF receptor signaling, can be in a cell or a multicellular organism. Ifin a multicellular organism, the method disclosed herein comprisesadministering to the organism a compound disclosed herein, or acomposition disclosed herein. In some embodiments, the organism is amammal; in other embodiments, the organism is a human. In still otherembodiments, the method further comprises contacting the kinase with anadditional therapeutic agent.

In another aspect, provided herein is a method of inhibitingproliferative activity of a cell, the method comprising contacting thecell with an effective proliferative inhibiting amount of a compounddisclosed herein or a composition thereof. In other embodiments, themethod further comprises contacting the cell with an additionaltherapeutic agent.

In another aspect, provided herein is a method of treating a cellproliferative disease in a patient, the method comprises administeringto the patient in need of such treatment an effective therapeutic amountof a compound disclosed herein or a composition thereof. In otherembodiments, the method further comprises administering an additionaltherapeutic agent.

In another aspect, provided herein is a method of inhibiting tumorgrowth in a patient, the method comprises administering to the patientin need thereof an effective therapeutic amount of a compound disclosedherein or a composition thereof. In other embodiments, the methodfurther comprises administering an additional therapeutic agent.

In another aspect, provided herein include methods of preparing, methodsof separating, and methods of purifying compounds of Formula (I), (IV)or (V).

The foregoing merely summarizes certain aspects disclosed herein and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below.

DETAILED DESCRIPTION OF THE INVENTION Definitions and GeneralTerminology

Reference will now be made in detail to certain embodiments disclosedherein, examples of which are illustrated in the accompanying structuresand formulas. The invention is intended to cover all alternatives,modifications, and equivalents that may be included within the scopedisclosed herein as defined by the claims. One skilled in the art willrecognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice disclosed herein.Described herein is in no way limited to the methods and materials. Inthe event that one or more of the incorporated literature, patents, andsimilar materials differ from or contradict this application, includingbut not limited to defined terms, term usage, described techniques, orthe like, this application controls.

As used herein, the following definitions shall be applied unlessotherwise indicated. For purposes disclosed herein, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, and the Handbook of Chemistry and Physics,75^(th) Ed. 1994. Additionally, general principles of organic chemistryare described in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry” byMichael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, theentire contents of which are hereby incorporated by reference.

As described herein, compounds may optionally be substituted with one ormore substituents, such as are illustrated generally above, or asexemplified by particular classes, subclasses, and species disclosedherein. It will be appreciated that the phrase “optionally substituted”is used interchangeably with the phrase “substituted or unsubstituted”.In general, the term “substituted” whether preceded by the term“optionally” or not, refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent. Unless otherwise indicated, an optionally substituted groupmay have a substituent at each substitutable position of the group. Whenmore than one position in a given structure can be substituted with morethan one substituent selected from a specified group, the substituentmay be either the same or different at each position.

The term “aliphatic” or “aliphatic group” as used herein, refers to astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 carbon atoms. In some embodiments,aliphatic groups contain 1-10 carbon atoms. In other embodiments,aliphatic groups contain 1-8 carbon atoms. In still other embodiments,aliphatic groups contain 1-6 carbon atoms, and in yet other embodiments,aliphatic groups contain 1-4 carbon atoms. Suitable aliphatic groupsinclude, but are not limited to, linear or branched, substituted orunsubstituted alkyl, alkenyl, or alkynyl groups.

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twenty carbonatoms, wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. Furtherexamples of aliphatic groups include, but are not limited to, methyl(Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃),2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl,—CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl(s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl,—C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl(—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl(—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl(—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl(—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl,1-octyl, and the like. The terms “alkyl” and the prefix “alk-” as usedherein, are inclusive of both straight chain and branched saturatedcarbon chain. The term “alkylene”, as used herein, represents asaturated divalent hydrocarbon group derived from a straight or branchedchain saturated hydrocarbon by the removal of two hydrogen atoms, and isexemplified by methylene, ethylene, isopropylene, and the like.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to twelve carbon atoms with at least one siteof unsaturation, i.e., a carbon-carbon, sp² double bond, wherein thealkenyl radical may be optionally substituted independently with one ormore substituents described herein, and includes radicals having “cis”and “trans” orientations, or alternatively, “E” and “Z” orientations.Examples include, but are not limited to, ethylenyl or vinyl (—CH═CH₂),allyl (—CH₂CH═CH₂), and the like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to twelve carbon atoms with at least one site ofunsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynylradical may be optionally substituted independently with one or moresubstituents described herein. Examples include, but are not limited to,ethynyl (—C≡CH), propynyl (propargyl, —CH₂C≡CH), and the like.

The term “cycloaliphatic” (or “carbocycle”, “carbocyclyl”, “carbocyclicring” and “cycloalkyl”) refers to a monovalent or multivalentnon-aromatic, saturated or partially unsaturated ring having 3 to 12carbon atoms as a monocyclic ring or 7 to 12 carbon atoms as a bicyclicring. Bicyclic carbocycles having 7 to 12 atoms can be arranged, forexample, as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, and bicycliccarbocycles having 9 or 10 ring atoms can be arranged as a bicyclo[5,6]or [6,6] system. Suitable cycloaliphatic groups include, but are notlimited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Further examplesof cycloaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, and the like.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or“heterocyclic” as used interchangeably herein refers to a monocyclic,bicyclic, or tricyclic ring system in which one or more ring members arean independently selected heteroatom and that is completely saturated orthat contains one or more units of unsaturation, but which is notaromatic, that has a single point of attachment to the rest of themolecule. One or more ring atoms are optionally substitutedindependently with one or more substituents described below. In someembodiments, the “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”or “heterocyclic” group is a monocycle having 3 to 7 ring members (e.g.,1 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P or S,wherein the S or P is optionally substituted with one or more oxo toprovide the group SO or SO₂, PO or PO₂, with the proviso that when thering is a 3-membered ring, there is only one heteroatom) or a bicyclehaving 7 to 10 ring members (e.g., 4 to 9 carbon atoms and 1 to 3heteroatoms selected from N, O, P or S, wherein the S or P is optionallysubstituted with one or more oxo to provide the group SO or SO₂, PO orPO₂).

The heterocyclyl may be a carbon radical or heteroatom radical.“Heterocyclyl” also includes radicals where heterocycle radicals arefused with a saturated, partially unsaturated ring, or heterocyclicring. Examples of heterocyclic rings include, but are not limited to,pyrrolidinyl, tetrahydrofliranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl,1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolylquinolizinyl and N-pyridyl ureas. Some non-limiting examples of aheterocyclic ring include 1,1-dioxo-thiomorpholinyl and heterocyclicgroup wherein 2 carbon atoms on the ring are substituted with oxo (═O)moieties are pyrimidindionyl. The heterocyclic groups herein areoptionally substituted independently with one or more substituentsdescribed herein.

The term “heterocyclylalkyl” refers to heterocyclic-substituted alkylradical. The term “heterocyclylalkoxy” refers toheterocyclic-substituted alkoxy radical wherein oxygen atom serves asthe attaching point to the rest of the molecule. The term“heterocyclylalkylamino” refers to heterocyclic-substituted alkylaminoradical wherein nitrogen atom serves as the attaching point to the restof the molecule. The term “heterocyclyloxy” refers toheterocyclic-substituted oxygen radical wherein oxygen atom serves asthe attaching point to the rest of the molecule. The terms“heterocyclylamino” and “heterocyclylalkylamino” refers toheterocyclic-substituted nitrogen radical and heterocyclic- andalkyl-substituted nitrogen radical wherein nitrogen atom serves as theattaching point to the rest of the molecule.

The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon, including any oxidized form of nitrogen, sulfur,or phosphorus; the quaternized form of any basic nitrogen; or asubstitutable nitrogen of a heterocyclic ring, for example, N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as inN-substituted pyrrolidinyl).

The term “halogen” refers to F, Cl, Br or I.

The term “unsaturated” as used herein, refers to that a moiety has oneor more units of unsaturation.

The term “alkoxy” as used herein, refers to an alkyl group, aspreviously defined, attached to the principal carbon chain through anoxygen (“alkoxy”) atom.

The terms “haloalkyl”, “haloalkenyl” or “haloalkoxy” refers to alkyl,alkenyl, or alkoxy, as the case may be, substituted with one or morehalogen atoms.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy” or “aryloxyalkyl” refers to monocyclic, bicyclic,and tricyclic carbocyclic ring systems having a total of six to fourteenring members, wherein at least one ring in the system is aromatic,wherein each ring in the system contains 3 to 7 ring members and thathas a single point of attachment to the rest of the molecule. The term“aryl” may be used interchangeably with the term “aryl ring”. Somenon-limiting examples of aryl rings include phenyl, naphthyl, andanthracene.

The term “heteroaryl” used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy” refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, wherein eachring in the system contains 3 to 7 ring members and that has a singlepoint of attachment to the rest of the molecule. The term “heteroaryl”may be used interchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

Some non-limiting examples of suitable heteroaryl rings include thefollowing monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl,4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl(e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl(e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, andthe following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl,indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl,3-quinolinyl, 4-quinolinyl), or isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, refers to respectively divalent radicals —SO₂—. The term“alkylsulfonyl”, refers to a sulfonyl radical substituted with an alkylradical, forming a alkylsulfonyl (—SO₂CH₃).

The terms “sulfamyl”, “aminosulfonyl” and “sulfonamidyl” refer to asulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂).

The term “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, refers to —CO₂H. The term “carbonyl”,whether used alone or with other terms, such as “aminocarbonyl” or“carbonyloxy”, refers to —(C═O)—.

The term “aralkyl” refers to aryl-substituted alkyl radicals. In someembodiments, aralkyl radicals are “lower aralkyl” radicals having arylradicals attached to alkyl radicals having one to six carbon atoms. Inother embodiments, aralkyl radicals are “phenylalkylenyl” attached toalkyl portions having one to three carbon atoms. Some non-limitingexamples of such radicals include benzyl, diphenylmethyl andphenylethyl. The aryl in said aralkyl can be additionally substitutedwith halo, alkyl, alkoxy, haloalkyl and haloalkoxy.

The term “alkylthio” refers to radicals containing a linear or branchedalkyl radical, of one to ten carbon atoms, attached to a divalent sulfuratom. In other embodiments alkylthio radicals are lower alkylthioradicals having one to three carbon atoms. Some non-limiting examples of“alkylthio” include methylthio (CH₃S—).

The term “haloalkylthio” refers to radicals containing a haloalkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.In other embodiments, haloalkylthio radicals are lower haloalkylthioradicals having one to three carbon atoms. Some non-limiting examples of“haloalkylthio” include trifluoromethylthio.

The term “alkylamino” refers to “N-alkylamino” and “N,N-dialkylamino”where amino groups are independently substituted with one alkyl radicalor with two alkyl radicals, respectively. In other embidiments,alkylamino radicals are “lower alkylamino” radicals having one or twoalkyl radicals of one to six carbon atoms, attached to a nitrogen atom.In still other embodiments, alkylamino radicals are lower alkylaminoradicals having one to three carbon atoms. Some non-limiting examples ofsuitable alkylamino radicals include mono or dialkylamino such asN-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, andthe like.

The term “arylamino” refers to amino groups, which have been substitutedwith one or two aryl radicals, Some non-limiting examples of arylaminoinclude N-phenylamino. In some embodiments, the arylamino radicalsinclude substituted on the aryl ring portion of the radical.

The term “heteroarylamino” refers to amino groups, which have beensubstituted with one or two heteroaryl radicals, Some non-limitingexamples of heteroarylamino include N-thienylamino. In otherembodiments, the “heteroarylamino” radicals include substituted on theheteroaryl ring portion of the radical.

The term “aminoalkyl” refers to linear or branched alkyl radicals havingone to about ten carbon atoms any one of which includes substituted withone or more amino radicals. In some embodiments, aminoalkyl radicals are“lower aminoalkyl” radicals having one to six carbon atoms and one ormore amino radicals. Some non-limiting examples of such radicals includeaminomethyl, aminoethyl, aminopropyl, aminobutyl or aminohexyl.

The term “alkylaminoalkyl” refers to alkyl radicals substituted withalkylamino radicals. In some embodiments, alkylaminoalkyl radicals are“lower alkylaminoalkyl” radicals having alkyl radicals of one to sixcarbon atoms. In other embodiments, alkylaminoalkyl radicals are loweralkylaminoalkyl radicals having alkyl radicals of one to three carbonatoms. Some non-limiting examples of suitable alkylaminoalkyl radicalsinclude mono or dialkyl substituted, such as N-methylaminomethyl,N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl, and the like.

The term “alkylaminoalkoxy” refers to alkoxy radicals substituted withalkylamino radicals. Some non-limiting examples of suitablealkylaminoalkoxy radicals include mono or dialkyl substituted, such asN-methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy,and the like.

The term “alkylaminoalkoxyalkoxy” refers to alkoxy radicals substitutedwith alkylaminoalkoxy radicals. Some non-limiting examples of suitablealkylaminoalkoxyalkoxy radicals include mono or dialkyl substituted,such as N-methylaminomethoxyethoxy, N-methylaminoethoxyethoxy,N,N-dimethylaminoethoxyethoxy, N,N-diethylaminomethoxymethoxy, and thelike.

The term “carboxyalkyl” refers to linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which maybe substitutedwith one or more carboxy radicals. Some non-limiting examples of suchradicals include carboxymethyl, carboxypropyl, and the like.

The term “aryloxy” refers to optionally substituted aryl radicals, asdefined above, attached to an oxygen atom. Some non-limiting examples ofsuch radicals include phenoxy.

The term “heteroaryloxy” refers to optionally substituted heteroarylradicals, as defined above, attached to an oxygen atom.

The term “heteroarylalkoxy” refers to oxy-containing heteroarylalkylradicals attached through an oxygen atom to other radicals.

The term “cycloalkylalkyl” refers to cycloalkyl-substituted alkylradicals. Some non-limiting examples of such radicals includecyclohexylmethyl. The cycloalkyl in the radicals may be additionallysubstituted with halo, alkyl, alkoxy or hydroxy.

The terms “fused bicyclic”, “fused cyclic”, “fused bicyclyl” and “fusedcyclyl” refer to saturated bridged ring system, which refers to abicyclic ring system that is not aromatic. Such a system may containisolated or conjugated unsaturation, but not aromatic or heteroaromaticrings in its core structure (but may have aromatic substitutionthereon). Each cyclic ring in a fused bicyclyl can be either acarbocyclic or a heteroalicyclic. Some non-limiting examples of fusedbicyclic ring system include hexahydro-furo[3,2-b]furan,2,3,3a,4,7,7a-hexahydro-1H-indene, 7-azabicyclo[2.2.1]heptane, and1,2,3,4,4a,5,8,8a-octahydro-naphthalene.

The terms “spirocyclyl”, “spirocyclic”, “spiro bicyclyl” or “spirobicyclic” refer to a ring originating from a particular annular carbonof another ring. For example, as depicted below, a saturated bridgedring system (ring B and B') is termed as “fused bicyclic”, whereas ringA and ring B share an atom between the two saturated ring system, whichterms as a “spirocyclyl” or “spiro bicyclyl”. Each cyclic ring in aspirocyclyl can be either a carbocyclic or a heteroalicyclic.

As described herein, a bond drawn from a substituent to the center ofone ring within a ring system (as shown below) represents substitutionof the substituent at any substitutable position on the rings to whichit is attached. For example, Figure a represents possible substitutionin any of the positions on the B ring shown in Figure b.

As described herein, a dot line drawn together with a bond within a ringsystem (as shown in Figure c) represents either a double bond or asingle bond. For example, structure in Figure c represents anystructures selected from Figure d.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, orgeometric (or conformational) mixtures of the present compounds arewithin the scope disclosed herein.

The term “prodrug” as used herein, represents a compound that istransformed in vivo into a compound of Formula (I). Such atransformation can be affected, for example, by hydrolysis in blood orenzymatic transformation of the prodrug form to the parent form in bloodor tissue. Prodrugs of the compounds disclosed herein may be, forexample, esters. Esters that may be utilized as prodrugs in the presentinvention are phenyl esters, aliphatic (C₁-C₂₄) esters, acyloxymethylesters, carbonates, carbamates, and amino acid esters. For example, acompound disclosed herein that contains an OH group may be acylated atthis position in its prodrug form. Other prodrug forms includephosphates, such as, for example those phosphates resulting from thephosphonation of an OH group on the parent compound. A thoroughdiscussion of prodrugs is provided in T. Higuchi and V. Stella,Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. SymposiumSeries, Edward B. Roche, ed., Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press, 1987, J. Rautioet al, Prodrugs: Design and Clinical Applications, Nature Review DrugDiscovery, 2008, 7, 255-270, and S. J. Hecker et al, Prodrugs ofPhosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51,2328-2345, each of which is incorporated herein by reference.

Unless otherwise stated, all tautomeric forms of the compounds disclosedherein are within the scope of the invention. Additionally, unlessotherwise stated, structures depicted herein are also meant to includecompounds that differ only in the presence of one or more isotopicallyenriched atoms.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound.Accordingly, the invention includes metabolites of compounds disclosedherein, including compounds produced by a process comprising contactinga compound disclosed herein with a mammal for a period of timesufficient to yield a metabolic product thereof.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds disclosed herein may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds disclosedherein, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand 1 or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or/meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.Some non-limiting examples of proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

A “pharmaceutically acceptable salt” as used herein, refers to organicor inorganic salts of a compound disclosed herein. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19, 1977, which is incorporated herein byreference. Examples of pharmaceutically acceptable, nontoxic acidaddition salts include, but are not limited to, salts of an amino groupformed with inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid and perchloric acid or with organic acidssuch as acetic acid, oxalic acid, maleic acid, tartaric acid, citricacid, succinic acid or malonic acid or by using other methods used inthe art such as ion exchange. Other pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,nitrate, oleate, palmitate, pamoate, pectinate, persulfate,3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺ (C₁₋₄ alkyl)₄ salts. Thisinvention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Water oroil-soluble or dispersable products may be obtained by suchquaternization. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, C₁₋₈ sulfonate or aryl sulfonate.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound disclosed herein. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.The term “hydrate” refers to the complex where the solvent molecule iswater.

The term “protecting group” or “Pg” refers to a substituent that iscommonly employed to block or protect a particular functionality whilereacting other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound. Somenon-limiting examples of suitable amino-protecting groups includeacetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz)and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Some non-limitingexamples of suitable hydroxy-protecting groups include acetyl and silyl.A “carboxy-protecting group” refers to a substituent of the carboxygroup that blocks or protects the carboxy functionality. Somenon-limiting examples of common carboxy-protecting groups include—CH₂CH₂SO₂Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxy methyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenyl phosphino)-ethyl,nitroethyl, and the like. For a general description of protecting groupsand their use, see T. W. Greene, Protective Groups in Organic Synthesis,John Wiley & Sons, New York, 1991; and P. J. Kocienski, ProtectingGroups, Thieme, Stuttgart, 2005.

DESCRIPTION OF COMPOUNDS OF THE INVENTION

Disclosed herein are heterocyclic compounds, and pharmaceuticalformulations thereof, that are potentially useful in the treatment ofdiseases, conditions and/or disorders modulated by protein kinases,especially KDR, c-Met receptor and/or IGF receptor. More specifically,provided herein include compounds of Formula (I):

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, ahydrate, a solvate, a metabolite, a pharmaceutically acceptable salt ora prodrug thereof, wherein each of R³, U₁, X₁, Q₁ and Q₂ is as definedherein.

In certain embodiments, Q₁ is Formula (IIa) or (IIb):

wherein each of V, V₁, V₂, V₃, V₄, X₂, X₃, Z, Z₁, and Z₂ is as definedherein; and Q₂ is Formula (III):

wherein each of R¹, R², W₁, W₂, W₃, W₄ and U₂ is as defined herein.

In some embodiments, the compounds have Formula (IV) or (V):

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, ahydrate, a solvate, a metabolite, a pharmaceutically acceptable salt ora prodrug thereof, wherein each of R³, U₁, V, V₁, V₂, V₃, V₄, X₁, X₂,X₃, Z, Z₁, Z₂ and Q₂ is as defined herein, wherein:

each of R¹ and R² is independently H, halo, cyano(CN), hydroxyl,R^(5a)R⁵N—, —C(═O)NR⁵R^(5a), —OC(═O)NR⁵R^(5a), —OC(═O)OR⁵,—NR⁵C(═O)NR⁵R^(5a), —NR⁵C(═O)OR^(5a), —NR⁵C(═O)R^(5a), R⁵R^(5a)N—O₂S—,R⁵O₂S—, R⁵O₂S—R^(5a)N—, R^(5a)R⁵N-alkyl, R⁵S(═O)_(r)-alkyl,R⁵R^(5a)N—C(═O)alkyl, R^(5a)R⁵N-alkoxy, R⁵S(═O)_(r)-alkoxy,R⁵R^(5a)N—C(═O)-alkoxy, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy,hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substitutedhaloalkoxy, alkylamino haloalkoxy, hydroxy-substituted haloalkoxy,alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy,carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy),carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy,heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy,cycloalkyloxy, (heterocyclo)hydroxyalkoxy, azidoalkoxy, fused bicyclyl,fused heterobicyclyl, fused bicyclyl aliphatic, fused heterobicyclylaliphatic, fused bicycloxy, fused heterobicycloxy, fused bicyclylamino,fused heterobicyclylamino, fused bicycloxoalkoxy, fusedheterobicycloxoalkoxy, fused bicyclyl aminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl-C(═O)—, fused bicyclyl-C(═O)O—, fusedheterobicyclyl-C(═O)—, fused heterobicyclyl-C(═O)O—, fusedbicyclylamino-C(═O)—, fused heterobicyclylamino-C(═O)—, fusedbicyclyl-C(═O)NR⁵—, fused heterobicyclyl-C(═O)NR⁵—, spiro bicyclyl,spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclylaliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino,spiro heterobicyclylamino, spiro bicycloxoalkoxy, spiroheterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spiro bicyclyl —C(═O)—, spirobicyclyl-C(═O)O—, spiro heterobicyclyl-C(═O)—, spiroheterobicyclyl-C(═O)O—, spiro bicyclylamino-C(═O)—, spiroheterobicyclylamino-C(═O)—, spiro bicyclyl-C(═O)NR⁵—, or spiroheterobicyclyl-C(═O)NR⁵—, aryl, heteroaryl, arylaliphatic,heteroarylaliphatic; and each of alkoxy and alkylamino moiety isindependently substituted with one or more hydroxy groups, amino groupsor substituted amino groups;

each of R³ and R^(3a) is one or more substituents independently H, F,Cl, Br, I, —CN, hydroxyl, R^(5a)R⁵N—, R^(5a)R⁵N-aliphatic,hydroxyaliphatic, aliphatic, alkoxy, alkoxyaliphatic, haloalkyl,heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkoxy aliphatic,heterocycloxy aliphatic, cycloalkylalkoxy, heterocyclylalkoxy,aryloxyalkyl, heteroaryloxy aliphatic, arylaliphatic, heteroarylaliphatic, aryl, or heteroaryl.

each of U₁ and U₂ is independently CR⁴ or N;

V is NR⁵R^(5a), OR⁵, aliphatic, cycloalkyl, heterocyclyl, aryl,heteroaryl, arylaliphatic or heteroarylaliphatic;

V₁ is O or NR⁵;

each of V₂, V₃, V₄ is independently CR⁴R^(4a), NR⁵, CR⁴ or N, with theproviso that only one of V₂, V₃ and V₄ is NR⁵ or N; V₂ and V₃ or V₃ andV₄ may combine to become CR⁴R^(4a), NR⁵, O, CR⁴ or N, with the provisothat the resulted structures are stable;

each of W₁, W₂, W₃, W₄ is independently CR⁴R^(4a), NR⁵, CR⁴ or N; W₁ andW₂ or W₃ and W₄ may combine to become CR⁴R^(4a), NR⁵, O or S;

X₁ is (CR⁴R^(4a))_(m), NR⁵, O, S, S═O or SO₂; m is 0, 1, or 2;

each of X₂ and X₃ is independently O, S or NR⁵;

Z is —NR⁵C(═O)(CR⁴R^(4a))_(p)—, —NR⁵C(═S)(CR⁴R^(4a))_(p)—,—NR^(5a)(CR⁴R^(4a))_(p)—, —NR⁵ (CR⁴R^(4a))_(p)C(═O)—, —NR⁵(CR⁴R^(4a))_(p)C(═S)—, —NR⁵S(═O)_(r)—, —NR⁵S(═O)_(r)(CR⁴R^(4a))_(p)—,—C(═O)NR⁵(CR⁴R^(4a))_(p)— or —NR⁵ (CR⁴R^(4a))_(p)S(═O)_(r)—, where p is0, 1, 2 or 3; and r is 1, or 2;

each of Z₁ and Z₂ is independently NR⁵ or CR⁴R^(4a);

each of R⁴ and R^(4a) is independently H, F, Cl, Br, I, —CN, hydroxyl,—NR^(5a)R⁵, alkoxy, cycloalkoxy, heterocycloalkoxy, aliphatic,haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic,alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic,heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic,heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic,heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl,heterocyclyl or carbocyclyl, with the proviso that where R⁴ and R^(4a)are bonded to the same carbon atom, R⁴ and R^(4a), together with thecarbon atom they are attached to, optionally form a substituted orunsubstituted 3-8 membered carbocyclic or heterocyclic ring;

each of R⁵ and R^(5a) is independently H, R⁶R^(6a)NC(═O)—, R⁶OC(═O)—,R⁶C(═O)—, R⁶R^(6a)NS(═O)—, R⁶OS(═O)—, R⁶S(═O)—, R⁶R^(6a)NSO₂—, R⁶OSO₂—,R⁶SO₂—, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic,alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic,heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic,heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic,heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl,heterocyclyl or carbocyclyl, with the proviso that where R⁵ and R^(5a)are bonded to the same nitrogen atom, R⁵ and R^(5a), together with thenitrogen atom they are attached to, optionally form a substituted orunsubstituted 3-8 membered ring, including spiro and fused bicyclicrings; and

each of R⁶ and R^(6a) is independently H, aliphatic, haloaliphatic,hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic,alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic,cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic,cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl, carbocyclyl.

In some embodiments, each of R^(5a)R⁵N—, —C(═O)NR⁵R^(5a),—OC(═O)NR⁵R^(5a), —OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a), —NR⁵C(═O)OR^(5a),—NR⁵C(═O)—R^(5a), R⁵R^(5a)N—O₂S—, R⁵O₂S—, R⁵O₂SR^(5a)N—, OR⁵, NR⁵,CR⁴R^(4a), CR⁴, (CR⁴R^(4a))_(m), —NR⁵C(═O)—(CR⁴R^(4a))_(p)—,—NR⁵C(═S)—(CR⁴R^(4a))_(p)—, —NR^(5a)—(CR⁴R^(4a))_(p)—,—NR⁵—(CR⁴R^(4a))_(p)C(═O)—, —NR⁵—(CR⁴R^(4a))_(p)C(═S)—, —NR⁵S(O)_(r)—,—NR⁵S(═O)_(r)—(CR⁴R^(4a))_(p)—, —C(═O)NR⁵—(CR⁴R^(4a))_(p)— or—NR⁵—(CR⁴R^(4a))_(p)—S(═O)_(r)—, R^(5a)R⁵N-alkyl, R⁵S(═O)_(r)-alkyl,R⁵R^(5a)N—C(═O)-alkyl, R^(5a)R⁵N-alkoxy, R⁵S(═O)_(r)-alkoxy,R⁵R^(5a)N—C(═O)-alkoxy, R⁶R^(6a)NC(═O)—, R⁶OC(═O)—, R⁶C(═O)—,R⁶R^(6a)NS(═O)—, R⁶OS(═O)—, R⁶S(═O)—, R⁶R^(6a)NSO₂—, R⁶OSO₂—, R⁶SO₂—,aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy, hydroxy-substitutedaminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylaminohaloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy,alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy,heterocyclyl(hydroxyalkoxy), carbocyclyl(hydroxyalkoxy),aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy,carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy,(heterocyclo)hydroxyalkoxy, azidoalkoxy, fused bicyclyl, fusedheterobicyclyl, fused bicyclyl aliphatic, fused heterobicyclylaliphatic, fused bicycloxy, fused heterobicycloxy, fused bicyclylamino,fused heterobicyclylamino, fused bicycloxoalkoxy, fusedheterobicycloxoalkoxy, fused bicyclyl aminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl-C(═O)—, fused bicyclyl-C(═O)O—, fusedheterobicyclyl-C(═O)—, fused heterobicyclyl-C(═O)O—, fusedbicyclylamino-C(═O)—, fused heterobicyclylamino-C(═O)—, fusedbicyclyl-C(═O)NR⁵—, fused heterobicyclyl-C(═O)NR⁵—, spiro bicyclyl,spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclylaliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino,spiro heterobicyclylamino, spiro bicycloxoalkoxy, spiroheterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spiro bicyclyl —C(═O)—, spirobicyclyl-C(═O)O—, spiro heterobicyclyl-C(═O)—, spiroheterobicyclyl-C(═O)O—, spiro bicyclylamino-C(═O)—, spiroheterobicyclylamino-C(═O)—, spiro bicyclyl-C(═O)NR⁵—, or spiroheterobicyclyl-C(═O)NR⁵—, aryl, heteroaryl, arylaliphatic andheteroarylaliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic,alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic,heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic,heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic,heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, heterocyclyl andcarbocyclyl is independently substituted or unsubstituted.

In another embodiment, each of R¹ and R² is independently H, halo,cyano(CN), hydroxyl, R^(5a)R⁵N—, —C(═O)NR⁵R^(5a), —OC(═O)NR⁵R^(5a),—OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a), —NR⁵C(═O)OR^(5a), —NR⁵C(═O)—R^(5a),R⁵R^(5a)N—O₂S—, R⁵O₂S—, R⁵O₂SR^(5a)N—, R^(5a)R⁵N—C₁₋₆ alkyl,R⁵S(═O)_(r)—C₁₋₆ alkyl, R⁵R^(5a)N—C(═O)—C₁₋₆ alkyl, R^(5a)R⁵N—C₁₋₆alkoxy, R⁵S(═O)_(r)-alkoxy, R⁵R^(5a)N—C(═O)-alkoxy, optionallysubstituted C₁₋₆ aliphatic, optionally substituted C₁₋₆ alkylamino-C₁₋₆alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, optionally substituted C₃₋₁₀heterocyclyl-C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkoxy, C₁₋₆alkylthio-C₁₋₃alkoxy, —C₁₋₆ alkoxy-NR^(5a)—C(═O)—OR⁵, —C₁₋₃alkoxy-NR^(5a)—C(═O)—R⁵, —C₁₋₃ alkoxy-C(═O)—C₁₋₃ alkyl, C₁₋₆ alkoxy,hydroxy-C₁₋₆ alkoxy, amino-C₁₋₆ alkoxy, hydroxy-substituted amino-C₁₋₆alkoxy, C₁₋₆ haloalkoxy, amino-substituted-C₁₋₆haloalkoxy, C₁₋₆alkylamino-C₁₋₆haloalkoxy, hydroxy-substituted-C₁₋₆ haloalkoxy, C₁₋₆alkylamino-C₁₋₆ alkoxy, aryl-C₁₋₆ alkoxy, optionally substituted C₄₋₁₀heterocyclyl-C₁₋₆ alkoxy, optionally substituted C₄₋₁₀ cycloalkyl-C₁₋₆alkoxy, optionally substituted C₄₋₁₀ heterocyclyl(hydroxy-C₁₋₆ alkoxy),optionally substituted C₃₋₁₀ cycloalkyl(hydroxy-C₁₋₆ alkoxy),aryl(hydroxy-C₁₋₆ alkoxy), aryloxy-C₁₋₆ alkoxy, optionally substitutedC₄₋₁₀ heterocyclyloxy-C₁₋₆ alkoxy, optionally substituted C₃₋₁₀cycloalkyloxy-C₁₋₆ alkoxy, optionally substituted C₆₋₁₀ aryloxy,optionally substituted C₄₋₁₀ heterocyclyloxy, optionally substitutedC₃₋₁₀ cycloalkyloxy, optionally substituted C₄₋₁₀(heterocyclo)hydroxy-C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, azido-C₁₋₆ alkoxy,optionally substituted aryl-C₁₋₆ alkoxy, optionally substitutedC₁₋₆-alkoxy, optionally substituted C₃₋₇ cycloalkoxy, optionallysubstituted C₄₋₁₀ heterocycloalkoxy, optionally substituted C₆₋₁₀heteroarylalkoxy, optionally substituted C₅₋₁₂ fused bicyclyl,optionally substituted C₅₋₁₂ fused heterobicyclyl, optionallysubstituted C₅₋₁₂ fused bicyclyl C₁₋₃ aliphatic, optionally substitutedC₅₋₁₂ fused heterobicyclyl C₁₋₃ aliphatic, optionally substituted C₅₋₁₂fused bicycloxy, optionally substituted C₅₋₁₂ fused bicyclylamino,optionally substituted C₅₋₁₂ fused bicycloxo C₁₋₆-alkoxy, optionallysubstituted C₅₋₁₂ fused bicyclylamino C₁₋₆ alkoxy, optionallysubstituted C₅₋₁₂ fused bicyclyl-C(═O)—, optionally substituted C₅₋₁₂fused bicyclyl-C(═O)O—, optionally substituted C₅₋₁₂ fusedheterobicyclyl-C(═O)—, optionally substituted C₅₋₁₂ fusedheterobicyclyl-C(═O)O—, optionally substituted C₅₋₁₂ fusedbicyclylamino-C(═O)—, optionally substituted C₅₋₁₂ fusedheterobicyclylamino-C(═O)—, optionally substituted C₅₋₁₂ fusedbicyclyl-C(═O)NR⁵—, optionally substituted C₅₋₁₂ fusedheterobicyclyl-C(═O)NR⁵—, optionally substituted C₅₋₁₂ spiro bicyclyl,optionally substituted C₅₋₁₂ spiro heterobicyclyl, optionallysubstituted C₅₋₁₂ spiro bicyclyl C₁₋₃ aliphatic, optionally substitutedC₅₋₁₂ spiro heterobicyclyl C₁₋₃ aliphatic, optionally substituted C₅₋₁₂spiro bicycloxo C₁₋₆ alkoxy, optionally substituted C₅₋₁₂ spirobicyclylamino C₁₋₆ alkoxy, optionally substituted C₅₋₁₂ spiro bicycloxy,optionally substituted C₅₋₁₂ spiro bicyclylamino, optionally substitutedC₅₋₁₂ fused heterobicycloxy, optionally substituted C₅₋₁₂ fusedheterobicyclylamino, optionally substituted C₅₋₁₂ fused heterobicycloxoC₁₋₆ alkoxy, optionally substituted C₅₋₁₂ fused heterobicyclylamino C₁₋₆alkoxy, optionally substituted C₅₋₁₂ spiro heterobicycloxo C₁₋₆ alkoxy,optionally substituted C₅₋₁₂ spiro heterobicyclylamino C₁₋₆ alkoxy,optionally substituted C₅₋₁₂ spiro heterobicycloxy, optionallysubstituted C₅₋₁₂ spiro heterobicyclylamino, optionally substitutedC₅₋₁₂ spiro bicyclyl-C(═O)—, optionally substituted C₅₋₁₂ spirobicyclyl-C(═O)O—, optionally substituted C₅₋₁₂ spiroheterobicyclyl-C(═O)—, optionally substituted C₅₋₁₂ spiroheterobicyclyl-C(═O)O—, optionally substituted C₅₋₁₂ spirobicyclylamino-C(═O)—, optionally substituted C₅₋₁₂ spiroheterobicyclylamino-C(═O)—, optionally substituted C₅₋₁₂ spirobicyclyl-C(═O)NR⁵—, or optionally substituted C₅₋₁₂ spiroheterobicyclyl-C(═O)NR⁵—, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₁₋₁₀ heteroaryl, optionally substituted C₆₋₁₀ aryl C₁₋₆aliphatic or optionally substituted C₁₋₁₀ heteroaryl C₁₋₆ aliphatic; andeach of the above-mentioned alkoxy and alkylamino moiety maybeindependently substituted amino groups;

each of R³ and R^(3a) is independently H, F, Cl, Br, I, —CN, hydroxyl,R^(5a)R⁵N—, R^(5a)R⁵N—C₁₋₃aliphatic, hydroxy C₁₋₃aliphatic,C₁₋₃aliphatic, C₁₋₃alkoxy, C₁₋₃alkoxy C₁-3aliphatic, C₁₋₃haloalkyl,C₃₋₆heterocyclyl, C₃₋₆heterocyclyl C₁₋₃alkyl, C₃₋₆cycloalkyl,C₃₋₆cycloalkoxy C₁₋₃aliphatic, C₃₋₆heterocycloxy C₁₋₃aliphatic,C₁₋₃cycloalkyl C₁₋₃alkoxy, C₃₋₆heterocyclyl C₁₋₃alkoxy, C₆₋₁₀aryloxyC₁₋₃alkyl, C₁₋₁₀heteroaryloxy C₁₋₃aliphatic, aryl C₁₋₃aliphatic,C₁₋₁₀heteroaryl C₁₋₃aliphatic, C₆₋₁₀aryl, or C₁₋₁₀heteroaryl;

each of U₁ and U₂ is independently CR⁴, or N; and

V is NR⁵R^(5a), optionally substituted C₁₋₆ aliphatic, optionallysubstituted C₆₋₁₀ aryl, optionally substituted C₆₋₁₀ heteroaryl,optionally substituted C₆₋₁₀ aryl C₁₋₆ aliphatic, or optionallysubstituted C₆₋₁₀ heteroaryl C₁₋₆ aliphatic.

In another embodiment, formula (IIa) is

wherein R^(3a), R⁵, and R^(5a) are as defined herein.

In another embodiment, Q₂ is:

wherein R¹, R² and R⁵ are as defined herein.

In another embodiment, X₁ is O, or NR⁵;

Z is —NH—C(═O)—; and

each of Z₁ and Z₂ is independently NR⁵ or CR⁴R^(4a); with the provisothat R⁴ and R^(4a), together with the carbon atom they are attached to,may optionally form a substituted or unsubstituted 3-8 memberedcarbocyclic or heterocyclic ring.

In another embodiment, the substructure defined by X₁, Z, U₁ and R₃ isone of the following formulae:

In another embodiment, Formula (IIb) is:

wherein Ar is substituted or unsubstituted aryl or heteroaryl; and s is0 or 1.

In another embodiment, R¹ has one of the following structures:

wherein each of X₄ and X₄′ is independently (CR⁴R^(4a))_(m), NR⁵, O, S,S═O or SO₂;

each of m and n is independently 0, 1 or 2; and t is 1, 2, or 3.

In another embodiment, non-limiting examples of compounds disclosedherein, and their pharmaceutically acceptable salts and solvatesthereof, are shown in the following:

Provided herein includes the use of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment either acutely or chronically of anangiogenesis mediated disease state, including those described herein.The compounds disclosed herein are useful in the manufacture of ananti-cancer medicament. The compounds disclosed herein are also usefulin the manufacture of a medicament to attenuate, prevent, manage ortreat disorders through inhibition of KDR, c-Met and/or IGF1R. Alsoprovided herein is a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), (IV) or(V) in association with at least one pharmaceutically acceptablecarrier, adjuvant or diluent.

Also provided herein is a method of treating angiogenesis relateddisorders in a subject having or susceptible to such disorder, themethod comprising treating the subject with a therapeutically effectiveamount of a compound of Formula (I), (IV) or (V).

Unless otherwise stated, all stereoisomers, geometric isomers,tautomers, solvates, metabolites, salts, and pharmaceutically acceptableprodrugs of the compounds disclosed herein are within the scope of theinvention.

In certain embodiments, the salt is a pharmaceutically acceptable salt.The phrase “pharmaceutically acceptable” refers to that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The compounds disclosed herein also include salts of such compoundswhich are not necessarily pharmaceutically acceptable salts, and whichmay be useful as intermediates for preparing and/or purifying compoundsof Formula (I), (IV) or (V) and/or for separating enantiomers ofcompounds of Formula (I), (IV) or (V).

If the compound disclosed herein is a base, the desired salt may beprepared by any suitable method available in the art, for example,treatment of the free base with an inorganic acid, such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like, or with an organic acid, such as acetic acid, maleic acid,succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such asglucuronic acid or galacturonic acid, an alpha hydroxy acid, such ascitric acid or tartaric acid, an amino acid, such as aspartic acid orglutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid,a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid,and the like.

If the compound disclosed herein is an acid, the desired salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide or alkaline earth metalhydroxide, and the like. Illustrative examples of suitable saltsinclude, but are not limited to, organic salts derived from amino acids,such as glycine and arginine, ammonia, primary, secondary, and tertiaryamines, and cyclic amines, such as piperidine, morpholine andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, lithium, and thelike.

Composition, Formulations and Administration of Compounds of theInvention

According to another aspect, the invention features pharmaceuticalcompositions that include a compound of Formula (I), (IV) or (V), acompound listed herein, or a compound named in Examples 1-28, and apharmaceutically acceptable carrier, adjuvant, or vehicle. The amount ofthe compound in the compositions disclosed herein is such that iseffective to detectably inhibit a protein kinase in a biological sampleor in a patient.

It will also be appreciated that certain of the compounds disclosedherein can exist in free form for treatment, or where appropriate, as apharmaceutically acceptable derivative thereof. Some non-limitingexamples of the pharmaceutically acceptable derivative includepharmaceutically acceptable prodrugs, salts, esters, salts of suchesters, or any other adduct or derivative which upon administration to apatient in need is capable of providing, directly or indirectly, acompound as otherwise described herein, or a metabolite or residuethereof.

As described above, the pharmaceutically acceptable compositionsdisclosed herein additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. In Remington: TheScience and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy,Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia ofPharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan,1988-1999, Marcel Dekker, New York, the contents of each of which isincorporated by reference herein, are disclosed various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds disclosedherein, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols such as propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants.

The compositions disclosed herein may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal, intraocular,intrahepatic, intralesional and intracranial injection or infusiontechniques. In some embodiments, the compositions are administeredorally, intraperitoneally or intravenously. Sterile injectable forms ofthe compositions disclosed herein include aqueous or oleaginoussuspension. These suspensions may be formulated according to techniquesknown in the art using suitable dispersing or wetting agents andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that includewater, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium.

For this purpose, any bland fixed oil includes synthetic mono- ordiglycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents that arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms mayalso be used for the purposes of formulation.

The pharmaceutically acceptable compositions disclosed herein includeorally administered in any orally acceptable dosage form including, butnot limited to, capsules, tablets, aqueous suspensions or solutions. Inthe case of tablets for oral use, carriers commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions disclosedherein include administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols. The pharmaceutically acceptable compositionsdisclosed herein also include administered topically, especially whenthe target of treatment includes areas or organs readily accessible bytopical application, including diseases of the eye, the skin, or thelower intestinal tract. Suitable topical formulations are readilyprepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used. For topicalapplications, the pharmaceutically acceptable compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds disclosed herein include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutically acceptable compositions canbe formulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may beformulated, e.g., as micronized suspensions in isotonic, pH adjustedsterile saline or other aqueous solution, or, In other embodiments, assolutions in isotonic, pH adjusted sterile saline or other aqueoussolution, either with or without a preservative such as benzylalkoniumchloride. Alternatively, for ophthalmic uses, the pharmaceuticallyacceptable compositions may be formulated in an ointment such aspetrolatum. The pharmaceutically acceptable compositions disclosedherein may also be administered by nasal aerosol or inhalation. Suchcompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and may be prepared as solutions insaline, employing benzyl alcohol or other suitable preservatives,absorption promoters to enhance bioavailability, fluorocarbons, and/orother conventional solubilizing or dispersing agents.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use. In order to prolong the effect of a compounddisclosed herein, it is often desirable to slow the absorption of thecompound from subcutaneous or intramuscular injection. This may beaccomplished by the use of a liquid suspension of crystalline oramorphous material with poor water solubility. The rate of absorption ofthe compound then depends upon its rate of dissolution that, in turn,may depend upon crystal size and crystalline form. Alternatively,dissolving or suspending the compound in an oil vehicle accomplishesdelayed absorption of a parenterally administered compound form.

Injectable depot forms are made by forming microencapsule matrices ofthe compound in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of compound topolymer and the nature of the particular polymer employed, the rate ofcompound release can be controlled. Some non-limiting examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds disclosedherein with suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol or a suppository wax which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid; b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate; h) absorbents such as kaolinand bentonite clay; and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms, the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain pacifying agents and canalso be of a composition that they release the active ingredient(s)only, or in other embodiments, in a certain part of the intestinaltract, optionally, in a delayed manner. Some non-limiting examples ofembedding compositions that can be used include polymeric substances andwaxes.

Dosage forms for topical or transdermal administration of a compounddisclosed herein include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, contemplatedherein is the use of transdermal patches, which have the added advantageof providing controlled delivery of a compound to the body. Such dosageforms can be made by dissolving or dispensing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate can be controlled by eitherproviding a rate controlling membrane or by dispersing the compound in apolymer matrix or gel.

The compounds disclosed herein are preferably formulated in dosage unitform for ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions disclosed herein will be decided by the attending physicianwithin the scope of sound medical judgment. The specific effective doselevel for any particular patient or organism will depend upon a varietyof factors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed, and like factors well known in the medical arts.

The amount of the compounds disclosed herein that may be combined withthe carrier materials to produce a composition in a single dosage formwill vary depending upon the host treated, the particular mode ofadministration. In other embodiments, the compositions should beformulated so that a dosage of between 0.01-300 mg/kg body weight/day ofthe inhibitor can be administered to a patient receiving thesecompositions.

Compounds disclosed herein can be administered as the solepharmaceutical agent or in combination with one or more other additionaltherapeutic (pharmaceutical) agents where the combination causes nounacceptable adverse effects. This may be of particular relevance forthe treatment of hyper-proliferative diseases such as cancer. In thisinstance, the compound disclosed herein can be combined with knowncytotoxic agents, signal transduction inhibitors, or with otheranti-cancer agents, as well as with admixtures and combinations thereof.As used herein, additional therapeutic agents that are normallyadministered to treat a particular disease, or condition, are known as“appropriate for the disease, or condition, being treated”. As usedherein, “additional therapeutic agents” refers to includechemotherapeutic agents and other anti-proliferative agents.

For example, chemotherapeutic agents or other antiproliferative agentsmay be combined with the compounds disclosed herein to treatproliferative disease or cancer. Examples of chemotherapeutic agents orother antiproliferative agents include HDAC inhibitors including, butare not limited to, SAHA, MS-275, MGO 103, and those described in WO2006/010264, WO 03/024448, WO 2004/069823, US 2006/0058298, US2005/0288282, WO 00/71703, WO 01/38322, WO 01/70675, WO 03/006652, WO2004/035525, WO 2005/030705, WO 2005/092899, and demethylating agentsincluding, but not limited to, 5-aza-dC, Vidaza and Decitabine and thosedescribed in U.S. Pat. Nos. 6,268,137, 5,578,716, 5,919,772, 6,054,439,6,184,211, 6,020,318, 6,066,625, 6,506,735, 6,221,849, 6,953,783,11,393,380.

In another embodiment disclosed herein, for example, chemotherapeuticagents or other anti-proliferative agents may be combined with thecompounds disclosed herein to treat proliferative diseases and cancer.Examples of known chemotherapeutic agents include, but are not limitedto, for example, other therapies or anticancer agents that may be usedin combination with the inventive anticancer agents disclosed herein andinclude surgery, radiotherapy (in but a few examples, gamma-radiation,neutron beam radiotherapy, electron beam radiotherapy, proton therapy,brachytherapy, and systemic radioactive isotopes, to name a few),endocrine therapy, taxanes (taxol, taxotere etc), platinum derivatives,biologic response modifiers (interferons, interleukins, and tumornecrosis factor (TNF), TRAIL receptor targeting, agents, to name a few),hyperthermia and cryotherapy, agents to attenuate any adverse effects(e.g., antiemetics), and other approved chemotherapeutic drugs,including, but not limited to, alkylating drugs (mechlorethamine,chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites(Methotrexate, Pemetrexed etc), purine antagonists and pyrimidineantagonists (6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine),spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel),podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics(Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine,Lomustine), inorganic ions (Cisplatin, Carboplatin), Cell cycleinhibitors (KSP mitotic kinesin inhibitors, CENP-E and CDK inhibitors),enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide,and Megestrol), Gleevec(TM), adriamycin, dexamethasone, andcyclophosphamide. Antiangiogenic agents (Avastin and others). Kinaseinhibitors (Imatinib (Gleevec), Sutent, Nexavar, Erbitux, Herceptin,Tarceva, Iressa and others). Agents inhibiting or activating cancerpathways such as the mTOR, HIF (hypoxia induced factor) pathways andothers. For a more comprehensive discussion of updated cancer therapiessee, http://www.nci.nih.gov/, a list of the FDA approved oncology drugsat http://www.fda.gov/cder/cancer/druglist-rame.htm, and The MerckManual, Eighteenth Ed. 2006, the entire contents of which are herebyincorporated by reference.

In another embodiment, the compounds disclosed herein can be combinedwith cytotoxic anti-cancer agents. Examples of such agents can be foundin the 13th Edition of the Merck Index (2001). These agents include, byno way of limitation, asparaginase, bleomycin, carboplatin, carmustine,chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine,dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine),epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea,ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine,6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone,prednisolone, prednisone, procarbazine, raloxifen, streptozocin,tamoxifen, thioguanine, topotecan, vinblastine, vincristine, orvindesine.

Other cytotoxic drugs suitable for use with the compounds disclosedherein include, but are not limited to, those compounds acknowledged tobe used in the treatment of neoplastic diseases, such as those forexample in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition, 1996, McGraw-Hill). These agents include,by no way of limitation, aminoglutethimide, L-asparaginase,azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemonophosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethylmelamine, uridine, or vinorelbine.

Other cytotoxic anti-cancer agents suitable for use in combination withthe compounds disclosed herein also include newly discovered cytotoxicprinciples, some examples of cytotoxic principles include, but are notlimited to, oxaliplatin, gemcitabine, capecitabine, epothilone and itsnatural or synthetic derivatives, temozolomide (Quinn et al., J. Clin.Oncology, 2003, 21(4), 646-651), tositumomab (Bexxar), trabedectin(Vidal et al., Proceedings of the American Society for ClinicalOncology, 2004, 23, abstract, 3181), and the inhibitors of the kinesinspindle protein Eg5 (Wood et al., Curr. Opin. Pharmacol. 2001, 1,370-377).

In another embodiment, the compounds disclosed herein can be combinedwith other signal transduction inhibitors. Of particular interest aresignal transduction inhibitors which target the EGFR family, such asEGFR, HER-2, and HER-4 (Raymond et al., Drugs, 2000, 60 (Supp1.1),15-23; Harari et al., Oncogene, 2000, 19 (53), 6102-6114), and theirrespective ligands. Examples of such agents include, by no way oflimitation, antibody therapies such as Herceptin (trastuzumab), Erbitux(cetuximab), Vectibix (panitumumab), and pertuzumab. Examples of suchtherapies also include, by no way of limitation, small-molecule kinaseinhibitors such as Iressa (Gefitinib), Tarceva (Erlotinib), Tykerb(Lapatinib) Canertinib (CI1033), AEE788 (Traxler et al., CancerResearch, 2004, 64, 4931-4941).

In another embodiment, the compounds disclosed herein can be combinedwith other signal transduction inhibitors targeting receptor kinases ofthe split-kinase domain families (VEGFR, FGFR, PDGFR, flt-3, c-kit,c-fins, and the like), and their respective ligands. These agentsinclude, by no way of limitation, antibodies such as Avastin(bevacizumab). These agents also include, by no way of limitation,small-molecule inhibitors such as Gleevec/Imanitib, Sprycel (Dasatinib),Tasigna (Nilotinib), Nexavar (Sorafenib), CHIR-265, Pazopanib(GW-786034), Recentin (Cediranib/AZD2171), Zactima (Vandetanib),Vatalanib (PTK787/ZK222584), Telatinib (BAY-579352), BMS-690514,BMS582664 (Brivanib), BMS540215, Axitinib (AG-013736). Motesanib(AMG706), Sutent (Sunitinib), ZD6474 (Hennequin et al., 92nd AACRMeeting, New Orleans, Mar. 24-28, 2001, abstract, 3152), Tivozanib(KRN-951) (Taguchi et al., 95th AACR Meeting, Orlando, FIa, 2004,abstract, 2575), CP-547, 632 (Beebe et al., Cancer Res. 2003, 63,7301-7309), CP-673, 451 (Roberts et al., Proceedings of the AmericanAssociation of Cancer Research, 2004, 45, abstract, 3989), CHIR-258 (Leeet al., Proceedings of the American Association of Cancer Research,2004, 45, abstract, 2130), MLN-518 (Shen et al., Blood, 2003, 102, 11,abstract, 476).

In another embodiment, the compounds disclosed herein can be combinedwith inhibitors of histone deacetylase. Examples of such agents include,by no way of limitation, suberoylanilide hydroxamic acid (SAHA), LAQ-824(Ottmann et al., Proceedings of the American Society for ClinicalOncology, 2004, 23, abstract, 3024), LBH-589 (Beck et al., Proceedingsof the American Society for Clinical Oncology, 2004, 23, abstract,3025), MS-275 (Ryan et al., Proceedings of the American Association ofCancer Research, 2004, 45, abstract, 2452), FR-901228 (Piekarz et al.,Proceedings of the American Society for Clinical Oncology, 2004, 23,abstract, 3028) and MGCDO103 (U.S. Pat. No. 6,897,220).

In another embodiment, the compounds disclosed herein can be combinedwith other anti-cancer agents such as proteasome inhibitors, and m-TORinhibitors. These include, by no way of limitation, bortezomib (Mackayet al., Proceedings of the American Society for Clinical Oncology, 2004,23, Abstract, 3109), and sirolimus (rapamycin), everolimus, temsirolimus(CCI-779) (Wu et al., Proceedings of the American Association of CancerResearch, 2004, 45, abstract, 3849). The compounds disclosed herein canbe combined with other anti-cancer agents such as topoisomeraseinhibitors, including but not limited to camptothecin.

Those additional agents may be administered separately from thecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with the compound disclosed herein in a single composition. Ifadministered as part of a multiple dosage regimen, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another which would result in the desired activity of theagents.

The amount of both the compound and the additional therapeutic agent (inthose compositions which comprise an additional therapeutic agent asdescribed above) that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. Normally, the amount ofadditional therapeutic agent present in the compositions disclosedherein will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. In other embodiment, the amount of additionaltherapeutic agent in the presently disclosed compositions will rangefrom about 50% to 100% of the amount normally present in a compositioncomprising that agent as the only therapeutically active agent. In thosecompositions which comprise an additional therapeutic agent, thatadditional therapeutic agent and the compound disclosed herein may actsynergistically.

Uses of the Compounds and Compositions of the Invention

The invention features pharmaceutical compositions that include acompound of Formula (I) or a compound listed herein, and apharmaceutically acceptable carrier, adjuvant, or vehicle. The amount ofcompound in the compositions disclosed herein is such that is effectiveto detectably inhibit a protein kinase, such as VEGFR/KDR, IGF/IGF1Rand/or c-Met inhibitory activity. The compounds disclosed herein areuseful in therapy as antineoplasia agents or to minimize deleteriouseffects of VEGF, IGF and/or HGF.

Compounds disclosed herein would be useful for, but not limited to, theprevention or treatment of proliferative diseases, conditions, ordisorders in a patient by administering to the patient a compound or acomposition disclosed herein in an effective amount. Such diseases,conditions, or disorders include cancer, particularly metastatic cancer,atherosclerosis, and lung fibrosis.

Compounds disclosed herein would be useful for the treatment ofneoplasia including cancer and metastasis, including, but not limitedto: carcinoma such as cancer of the bladder, breast, colon, kidney,liver, lung (including small cell lung cancer), esophagus, gall-bladder,ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (includingsquamous cell carcinoma); hematopoietic tumors of lymphoid lineage(including leukemia, acute lymphocitic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma);hematopoietic tumors of myeloid lineage (including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia); tumors of mesenchymal origin (including fibrosarcoma andrhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumorsof the central and peripheral nervous system (including astrocytoma,neuroblastoma, glioma and schwannomas); and other tumors (includingmelanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'ssarcoma).

The compounds also would be useful for treatment of opthalmologicalconditions such as corneal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injuryor infection, diabetic retinopathy, retrolental fibroplasia andneovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerativediseases such as gastric ulcer; pathological, but non-malignant,conditions such as hemangiomas, including infantile hemaginomas,angiofibroma of the nasopharynx and avascular necrosis of bone; anddisorders of the female reproductive system such as endometriosis. Thecompounds are also useful for the treatment of edema, and conditions ofvascular hyperpermeability.

The compounds disclosed herein are also useful in the treatment ofdiabetic conditions such as diabetic retinopathy and microangiopathy.The compounds disclosed herein are also useful in the reduction of bloodflow in a tumor in a subject. The compounds disclosed herein are alsouseful in the reduction of metastasis of a tumor in a subject.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like. In otherembodiments, animals include horses, dogs, and cats. As used herein, thecompounds disclosed herein include the pharmaceutically acceptablederivatives thereof.

Where the plural form is used for compounds, salts, and the like, thisis taken to refer to also a single compound, salt, and the like.

The treatment method that includes administering a compound orcomposition disclosed herein can further include administering to thepatient an additional therapeutic agent (combination therapy) selectedfrom: a chemotherapeutic or anti-proliferative agent, or ananti-inflammatory agent, wherein the additional therapeutic agent isappropriate for the disease being treated and the additional therapeuticagent is administered together with a compound or composition disclosedherein as a single dosage form or separately from the compound orcomposition as part of a multiple dosage form. The additionaltherapeutic agent may be administered at the same time as a compounddisclosed herein or at a different time. In the latter case,administration may be staggered by, for example, 6 hours, 12 hours, 1day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.

The invention also features a method of inhibiting the growth of a cellthat expresses VEGFR, IGF1R or c-Met, that includes contacting the cellwith a compound or composition disclosed herein, thereby causinginhibition of growth of the cell. Examples of a cell whose growth can beinhibited include: a breast cancer cell, a colorectal cancer cell, alung cancer cell, a papillary carcinoma cell, a prostate cancer cell, alymphoma cell, a colon cancer cell, a pancreatic cancer cell, an ovariancancer cell, a cervical cancer cell, a central nervous system cancercell, an osteogenic sarcoma cell, a renal carcinoma cell, ahepatocellular carcinoma cell, a bladder cancer cell, a gastriccarcinoma cell, a head and neck squamous carcinoma cell, a melanomacell, or a leukemia cell.

Provided herein a method of inhibiting VEGFR, IGF1R or c-Met kinaseactivity in a biological sample that includes contacting the biologicalsample with a compound or composition disclosed herein. The term“biological sample” as used herein, means a sample outside a livingorganism and includes, without limitation, cell cultures or extractsthereof; biopsied material obtained from a mammal or extracts thereof;and blood, saliva, urine, feces, semen, tears, or other body fluids orextracts thereof. Inhibition of kinase activity, particularly VEGFR,IGF1R or c-Met kinase activity, in a biological sample is useful for avariety of purposes known to one of skill in the art. Examples of suchpurposes include, but are not limited to, blood transfusion,organ-transplantation, biological specimen storage, and biologicalassays.

In certain embodiments disclosed herein, an “effective amount” or“effective dose” of the compound or pharmaceutically acceptablecomposition is that amount effective for treating or lessening theseverity of one or more of the aforementioned disorders. The compoundsand compositions, according to the method disclosed herein, may beadministered using any amount and any route of administration effectivefor treating or lessening the severity of the disorder or disease. Theexact amount required will vary from subject to subject, depending onthe species, age, and general condition of the subject, the severity ofthe infection, the particular agent, its mode of administration, and thelike. A compound or composition can also be administered with one ormore other therapeutic agents, as discussed above.

The compounds disclosed herein or pharmaceutical compositions thereofmay also be used for coating an implantable medical device, such asprostheses, artificial valves, vascular grafts, stents and catheters.Vascular stents, for example, have been used to overcome restenosis(re-narrowing of the vessel wall after injury). However, patients usingstents or other implantable devices risk clot formation or plateletactivation. These unwanted effects may be prevented or mitigated bypre-coating the device with a pharmaceutically acceptable compositioncomprising a compound disclosed herein.

Suitable coatings and the general preparation of coated implantabledevices are described in U.S. Pat. Nos. 6,099,562, 5886026, and 5304121,the contents of each of which are incorporated by reference herein. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccarides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics intothe composition. Implantable devices coated with a compound disclosedherein are another embodiment disclosed herein. The compounds may alsobe coated on implantable medical devices, such as beads, orco-formulated with a polymer or other molecule, to provide a “drugdepot” thus permitting the drug to be released over a longer time periodthan administration of an aqueous solution of the drug.

General Synthetic Procedures

Generally, the compounds disclosed herein may be prepared by methodsdescribed herein, wherein the substituents are as defined for formulas(I), (IV) or (V), above, except where further noted. The followingnon-limiting schemes and examples are presented to further exemplify theinvention.

Persons skilled in the art will recognize that the chemical reactionsdescribed may be readily adapted to prepare a number of other compoundsdisclosed herein, and alternative methods for preparing the compoundsdisclosed herein are deemed to be within the scope disclosed herein. Forexample, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by utilizing other suitable reagents known in the art other thanthose described, and/or by making routine modifications of reactionconditions. Alternatively, other reactions disclosed herein or known inthe art will be recognized as having applicability for preparing othercompounds disclosed herein.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, ArcoChemical Company and Alfa Chemical Company, and were used withoutfurther purification unless otherwise indicated. Common solvents werepurchased from commercial suppliers such as Shantou XiLong ChemicalFactory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., GuangzhouReagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., QingdaoTenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.

Anhydrous THF, dioxane, toluene, and ether were obtained by refluxingthe solvent with sodium. Anhydrous CH₂Cl₂ and CHCl₃ were obtained byrefluxing the solvent with CaH₂. EtOAc, PE, hexane, DMA and DMF weretreated with anhydrous Na₂SO₄ prior use.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was conducted using a silica gel column. Silicagel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. ¹HNMR spectra were recorded with a Bruker 400 MHz spectrometer at ambienttemperature. ¹H NMR spectra were obtained as CDCl₃, d₆-DMSO, CD₃OD ord₆-acetone solutions (reported in ppm), using TMS (0 ppm) or chloroform(7.25 ppm) as the reference standard. When peak multiplicities arereported, the following abbreviations are used: s (singlet), d(doublet), t (triplet), m (multiplet), br (broadened), dd (doublet ofdoublets), dt (doublet of triplets). Coupling constants, when given, arereported in Hertz (Hz).

Low-resolution mass spectral (MS) data were determined on an Agilent1200 Series LCMS (Zorbax SB-C18, 2.1×30 mm, 4 micorn, 10 min, 0.6 mL/minflow rate, 5 to 95% (0.1% formic acid in CH₃CN) in (0.1% formic acid inH₂O) with UV detection at 210/254 nm and a low resonance electrospraymode (ESI).

Purities of compounds were assessed by Agilent 1100 Series highperformance liquid chromatography (HPLC) with UV detection at 210 nm and254 nm (Zorbax SB-C18, 2.1×30 mm, 4 micorn, 10 min, 0.6 mL/min flowrate, 5 to 95% (0.1% formic acid in CH₃CN) in (0.1% formic acid in H₂O).Column was operated at 40° C.

The following abbreviations are used throughout the specification:

-   HOAc acetic acid-   MeCN, CH₃CN acetonitrile-   NH₃ ammonia-   NH₄Cl ammonium chloride-   HBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   PyBop benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium    hexafluorophosphate-   Pd₂(dba)₃ bis(dibenzylideneacetone) palladium-   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   TEAC bis(tetra-ethylammonium)carbonate-   BBr₃ boron tribromide-   BSA bovine serum albumin-   Br₂ bromine-   BOC, Boc tert-butyloxycarbonyl-   Cs₂CO₃ cesium carbonate-   CHCl₃ chloroform-   CDCl₃ chloroform deuterated-   Cu copper-   CuI copper(I) iodide-   Et₂O diethyl ether-   DBU 1,8-diazabicyclo[5,4,0]undec-7-ene-   DIBAL diisobutylaluminum hydride-   DIAD diisopropyl azodicarboxylate-   DIEA diisopropylethylamine-   DEAD dimethyl azodicarboxylate-   DMF dimethylformamide-   DMAP 4-dimethylaminopyridine-   DMSO dimethylsulfoxide-   EDC, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide    hydrochloride-   dppa diphenylphosphoryl azide-   EtOAc ethyl acetate-   FBS fetal bovine serum g gram h hour-   HBr hydrobromic acid-   HCl hydrochloric acid-   HOBt 1-hydroxybenzotriazole hydrate-   H₂ hydrogen-   H₂O₂ hydrogen peroxide-   Fe iron-   LiHMDS lithium bis(trimethylsilyl)-amide-   LDA lithium diisopropylamide-   MCPBA meta-chloroperbenzoic acid-   MgSO₄ magnesium sulfate-   MeOH, CH₃OH methanol-   MeI methyl iodide-   CH₂Cl₂, DCM methylene chloride-   NMP N-methylpyrrolidinone-   mL, ml milliliter-   N₂ nitrogen-   Pd/C palladium on carbon-   Pd(OAc)₂ palladium acetate-   Pd(OH)₂ palladium hydroxide-   Pd(PPh₃)₄ palladium tetrakis triphenylphosphine-   Pd(dppf)Cl₂ 1,1-bis(diphenylphosphino)ferrocene palladium chloride-   PE petroleum ether (60-90° C.)-   PBS phosphate buffered saline-   POCl₃ phosphorous oxychloride-   K₂CO₃ potassium carbonate-   KOH potassium hydroxide-   RT, rt room temperature-   Rt retention time-   NaHCO₃ sodium bicarbonate-   NaBH₄ sodium borohydride-   NaBH₃CN sodium cyanoborohydride-   NaOtBu sodium tert-butoxide-   NaOH sodium hydroxide-   NaClO₂ sodium chlorite-   NaCl sodium chloride-   NaH₂PO₄ sodium dihydric phosphate-   NaH sodium hydride-   NaI sodium iodide-   Na₂SO₄ sodium sulfate-   TBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   THF tetrahydrofuran-   Et₃N, TEA triethylamine-   TFA trifluoroacetic acid-   P(t-bu)₃ tri(tert-butyl)phosphine-   NBS N-bromosuccinimide-   TBAI Tetrabutylammonium iodide-   H2O water

Substituted compounds 7, where W₁, W₂, W₃ and W₄ are CH, X₁ is 0; R¹(i.e. EO-), R⁵, and PG are as defined above, can be prepared by theprocess illustrated in Scheme 1. The substituted aryl 1 is nitrated togive compound 2 by a suitable nitration reagent such as HNO₃ atappropriate temperature such as 0° C. The NO₂ group is then reduced by areducing reagent such as Fe or Zn powder, or under hydrogenationcondition in the presence of Pd catalyst such as Pd/C. Aniline 3 iscondensed with a formate such as ethyl formate under basic condition togive substituted quinoline 4. Coupling of 4 with appropriate arylderivatives yields substituted diaryl ethers 5. The protecting group PGis removed to provide compound 6, which is condensed with E-L (L=asuitable leaving group such as OMs, Cl, Br or I; E=aliphatic,heterocyclic aliphatic, fused heterobicyclic aliphatic, spiroheterobicyclic aliphatic, cyclic aliphatic, fused bicyclic aliphatic,spiro bicyclic aliphatic, heterocyclic, fused heterobicyclic, spiroheterobicyclic, cyclic, fused bicyclic, spiro bicyclic, etc.) to afforddesired kinase inhibitor 7.

Alternatively, substituted indole/azaindole analogs 11 can besynthesized through the procedure depicted in Scheme 2. Where R¹, X₁, U₂and PG are as defined above, R is H, R^(5a)R⁵N—, aliphatic, alkoxy,haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkoxy or heterocyclylalkoxy. Substituted 2-aminopyrazole 8 isfirst transformed to 9 in a similar fashion as described in Scheme 1.The OH group is then replaced with a good leaving group L, such as Cl, For OMs. L in compound 10 is converted to a kinase inhibitor 11 in thepresence of base such as Cs₂CO₃, NaOH, DMAP, or lutidine in a solventsuch as dioxane, toluene, or DMA, etc. preferably at elevatedtemperature.

Alternatively, substituted kinase inhibitor 16 can be prepared using aprocess as demonstrated in Scheme 3. Where W₁, W₂, W₃, W₄, R¹ (i.e.EO-), R³, U₁, U₂, X₁ and PG are as defined above. Condensation of 12with a nitro-aryl derivative gives compound 13. Deprotection removes theprotecting group PG leading to compound 14. Attachment of E groupthrough a coupling process followed by the reduction of nitro groupaffords compound 15. Coupling of aniline 15 with an acid in the presenceof coupling reagent such as EDCI or HATU furnishes desired kinaseinhibitor 16.

Alternatively, kinase inhibitors in this invention can be obtainedthrough the process as described in Scheme 4. Where R¹ (i.e. EO-), R²and PG are as defined above. Thus, compound 20 is prepared through Pdcatalyzed amination of 2-chloropyridine derivative 19. Coupling ofaniline 20 with an acid followed by the removal of protecting group PGgives compound 22. An appropriate group such as spiro or bicyclic moietyis appended to the quinoline portion to yield compound 23. In the abovestructures, R is structures defined by V₁, V₂, V₃, and V₄ in Formula(IIa), or structures defined by Z₁, Z₂, X₂, and X₃ in Formula (IIb).

EXAMPLES Example 1N-(4-(7-(((5S)-4-methyl-4-azaspiro[2.4]heptane-5-yl)methoxy)quinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

Step 1) (S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)pyrrolidin-2-one

To a mixture of (S)-5-(hydroxymethyl)pyrrolidin-2-one (1.0 g, 8.7 mmol,Aldrich) and DHP (1.46 g, 17.4 mmol, Alfa) in 20 mL of dichloromethanewas added PPTS (0.437 g, 1.74 mmol, Aldrich) in portions. The reactionmixture was stirred at rt for 4 hrs, and was quenched with 20 mL ofsaturated NaHCO₃ aqueous solution. The resulted mixture was extractedwith dichloromethane (25 mL×2). The combined organic phases were driedover Na₂SO₄ and concentrated in vacuo. The residue was purified by asilica gel column chromatography (EtOAc) to give the title compound (asa diastereomer mixture) as colorless oil (0.9 g, 52%).

MS (ESI, pos. ion) m/z: 199.9 (M+1);

¹H NMR (400 MHz, CDCl₃): δ1.69-1.88 (m, 6H), 2.25-2.28 (m, 2H),2.32-2.35 (m, 2H), 3.23 (m, 1H), 3.48-3.55 (m, 2H), 3.78-3.85 (m, 2H),4.58 (m, 1H).

Step 2)(S)-1-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)pyrrolidin-2-one

To a mixture of NaH (0.48 g, 12 mmol, 60% mineral oil, Aldrich) in 15 mLof DMF was added a solution of(S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)pyrrolidin-2-one (2 g, 10mmol) in 5 mL of DMF via a syringe at −40° C. The reaction was stirredat −40° C. for 1 hr. CH₃I (0.9 mL, 12 mmol, Shanghai Jingchun ReagentLtd.) was added dropwise via a syringe. The reaction was continued tostir at −40° C. for 4 hrs, and was quenched with 10 mL of saturatedNaHSO₃ aqueous solution. The mixture was extracted with ethyl acetate(50 mL×3). The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (EtOAc) to give the desired product as colorless oil(1.98 g, 92%).

MS (ESI, pos. ion) m/z: 214.0 (M+1);

¹H NMR (400 MHz, CDCl₃): δ1.69-1.88 (m, 6H), 1.93-2.17 (m, 2H),2.33-2.47 (m, 2H), 2.90 (3H, s), 3.40-3.52 (m, 2H), 3.80-3.90 (m, 2H),3.78 (m, 1H), 4.60 (m, 1H).

Step 3)(5S)-4-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-azaspiro[2.4]heptane

To a mixture of(S)-1-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-pyrrolidin-2-one(0.6 g, 2.82 mmol) in 20 mL of THF was added Ti(Oi-Pr)₄ (2.56 mL, 8.45mmol, d=0.937 g/L, Aldrich) via a syringe under nitrogen at rt. Afterstirring at rt for 30 min, EtMgBr (5.63 mL, 16.9 mmol, 3M ethersolution, Aldrich) was added via a syringe pump over 3 hrs. The reactionwas continued to stir at rt overnight, and then quenched with a mixtureof 20 mL of water and 30 mL of ethyl acetate. After stirring for 20 min,the mixture was filtered through a celite pad. The filtrate wasextracted with ethyl acetate (30 mL×3). The combined organic phases weredried over Na₂SO₄ and concentrated in vacuo. The residue was purified bya silica gel column chromatography (50:1(v/v) CH₂Cl₂/CH₃OH) to afford(5S)-4-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-azaspiro[2.4]heptaneas pale yellow oil (64 mg, 10%).

MS (ESI, pos. ion) m/z: 226.0 (M+1);

¹H NMR (400 MHz, CDCl₃): δ0.23 (m, 1H), 0.46 (m, 1H), 0.63 (m, 1H), 0.86(m, 1H), 1.58-1.90 (m, 10H), 2.13 (s, 3H), 2.85 (m, 1H), 3.37-3.50 (m,2H), 3.72-3.89 (m, 2H), 4.62 (m, 1H).

Step 4) (5S)-4-methyl-5-(hydroxymethyl)-4-azaspiro[2.4]heptane

To a mixture of(5S)-4-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-azaspiro[2.4]heptane(64 mg, 0.284 mmol) in 10 mL of methanol was added4-methyl-benzenesulfonic acid (97.8 mg, 0.568 mmol, Aldrich). Thereaction mixture was stirred at 50° C. overnight, and then concentratedin vacuo. The residue was treated with 10 mL of saturated Na₂CO₃ aqueoussolution, and extracted with dichloromethane (20 mL×3). The combinedorganic phases were dried over Na₂SO₄ and concentrated in vacuo to givethe desired product as yellow oil (32 mg, 80%).

MS (ESI, pos. ion) m/z: 142.0 (M+1).

Step 5) ((5S)-4-methyl-4-azaspiro[2.4]heptane-5-yl)methylmethanesulfonate

A mixture of (5S)-4-methyl-5-(hydroxymethyl)-4-azaspiro[2.4]heptane (0.2g, 1.42 mmol) and triethylamine (0.287 g, 2.84 mmol, Shantou Xilongchemical factory) in 5 mL of dichloromethane was stirred at 0° C. for 30min. To the mixture was added methanesulfonyl chloride (0.325 g, 2.84mmol, Shanghai Haiqu chemical. Ltd.) via a syringe. The reaction mixturewas stirred at 0° C. for 4 hrs and quenched with a mixture of 5 mL ofsaturated Na₂CO₃ aqueous solution and 5 mL of water. The resultedmixture was extracted with dichloromethane (20 mL×3). The combinedorganic phases were dried over Na₂SO₄ and concentrated in vacuo to give((5S)-4-methyl-4-azaspiro[2.4]heptane-5-yl)methyl methanesulfonate asyellow oil (150 mg, 48%).

Step 6)N-(4-(7-(((5S)-4-methyl-4-azaspiro[2.4]heptane-5-yl)methoxy)quinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

To a mixture of ((5S)-4-methyl-4-azaspiro[2.4]heptane-5-yl)methylmethanesulfonate (150 mg, 0.685 mmol) andN-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide(331.5 mg, 0.685 mmol) in 8 mL of N,N-dimethylacetamide was added cesiumcarbonate (893 mg, 2.74 mmol, Aladdin). After stirring at 40° C. for 3days, the reaction mixture was concentrated in vacuo and the residue waschromatographed with a silica gel column (50:1 (v/v) CH₂Cl₂/CH₃OH) togive the desired product as a pale yellow solid (25 mg, 6%).

MS (ESI, pos. ion) m/z: 304.5 [(M/2)+1]; LC-MS Rt: 3.402 min;

¹H NMR (400 MHz, CDCl₃): δ0.32 (m, 1H), 0.52 (m, 1H), 0.71 (m, 1H), 0.92(m, 1H), 1.52 (m, 2H), 1.85 (m, 2H), 3.19 (m, 1H), 2.26 (s, 3H), 2.80(s, 3H), 3.37 (s, 3H), 4.11 (m, 1H), 4.22 (m, 1H), 6.40 (d, J=5.2 Hz,1H), 7.16 (t, J=8.4 Hz, 1H), 7.30 (m, 1H), 7.36 (m, 2H), 7.41 (m, 1H),7.48 (m, 2H), 7.56 (m, 2H), 7.91 (dd, J=12 Hz, 1H), 8.26 (d, J=9 Hz,1H), 8.58 (d, J=5 Hz, 1H), 10.88 (s, 1H).

Example 2N-(4-(7-(((5R)-4-oxaspiro[2.4]heptane-5-yl)methoxyl)quinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

Step 1) (S)-tetrahydro-5-oxofuran-2-carboxylic acid

To a solution of L-glutamic acid (10.07 g, 0.068 mol, J&K CHEMICA) in 20ml of concd. HCl and 40 mL H₂O was added a solution of NaNO₂ (7.0 g,0.102 mol, Shantou Xilong chemical factory) in H₂O (20 mL) slowly at −5°C. The mixture was continued to stir for 12 hrs at room temperature. Thereaction mixture was evaporated in vacuo below 50° C. to give yellowoil, which was dissolved in EtOAc. The solid formed was filtered andwashed with EtOAc. The filtrate and washing solution were combined,dried over Na₂SO₄. The solvent was concentrated in vacuo to give(S)-tetrahydro-5-oxofuran-2-carboxylic acid as pale yellow oil (8.1 g,91.6%)¹.

MS (ESI, pos. ion) m/z: 130.9 (M+1);

¹H NMR (400 MHz, CDCl₃): δ2.27-2.41 (m, 1H), 2.44-2.65 (m, 3H), 5.09 (m,1H), 9.12-9.55 (m, 1H).

Step 2) (S)-5-(hydroxymethyl)-dihydrofuran-2(3H)-one

To a solution of (S)-5-oxo-tetrahydrofuran-2-carboxylic acid (0.6 g,0.0046 mol) in 10.8 mL of THF was added BH₃.Me₂S solution (2.76 mL,0.0055 mol, 2 M in THF, Aldrich) dropwise via a syringe at −20° C. Themixture was stirred for 12 hrs at room temperature. The reaction wasthen quenched with aqueous NH₄Cl and extracted with EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo to furnish the crude product as light yellow oil.(S)-5-(Hydroxymethyl)-dihydrofuran-2(3H)-one was obtained as colorlessoil (0.253 g, 47%) after a silica gel column chromatography purification(100:1 (v/v) CHCl₃/MeOH)¹.

MS (ESI, pos. ion) m/z: 116.9 (M+1);

¹H NMR (400 MHz, CDCl₃): δ2.11-2.15 (m, 1H), 2.20-2.29 (m, 1H),2.46-2.51 (m, 2H), 3.63 (t, 2H), 3.83-3.86 (d, J=14.8 Hz, 1H), 4.58-4.63(m, 1H).

Step 3)(5S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-dihydrofuran-2(3H)-one

To a mixture of (S)-5-(hydroxymethyl)-dihydrofuran-2(3H)-one (1.78 g,0.0153 mol) and 3,4-dihydro-2H-pyran (2.62 g, 0.0312 mol, Alfa) in 40 mLof CH₂Cl₂ was added PPTS (0.391 g, 0.00156 mol, Aldrich) slowly. Afterstirring at rt overnight, the reaction mixture was quenched with 5 mL ofwater. The mixture was extracted with EtOAc (50 mL×2). The combinedorganic phases were dried over Na₂SO₄ and concentrated in vacuo to givepale yellow oil. The crude product was purified by a silica gel columnchromatography (3:1 (v/v) petroleum ether/EtOAc) to afford the titlecompound as colorless oil (2.7 g, 88%).

MS (ESI, pos. ion) m/z: 200.8 (M+1);

¹H NMR (400 MHz, CDCl₃): δ1.41-1.62 (m, 4H), 1.64-1.75 (m, 2H),2.11-2.19 (m, 1H), 2.22-2.31 (m, 1H), 2.39-2.49 (m, 1H), 2.51-2.62 (m,1H), 3.41-3.48 (m, 1H), 3.58-3.62 (dd, J₁=3.2 Hz, J₂=14.6 Hz, 1H),3.74-3.79 (m, 1H), 3.85-3.92 (dd, J₁=3.2 Hz, J₂=14.4 Hz, 1H), 4.55-4.72(m, 2H).

Step 4)1-((S)-3-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)butyl)cyclopropanol

To a mixture of Ti(OiPr)₄ (0.33 mL, 0.001 mol, Ardrich) and(5S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-dihydrofuran-2(3H)-one (1.0g, 0.005 mol) in 18.7 mL of THF was added a solution of 3M EtMgBr inEt₂O (4.3 mL, 0.0125 mol, Aldrich) via a syringe over 3 hrs at 15° C.After stirring for additional one hour at 15° C., the reaction wasquenched with 20 mL of saturated NH₄Cl solution, filtered and extractedwith EtOAc (50 mL×2). The combined organic phases were dried over Na₂SO₄and concentrated in vacuo. The residue was purified by a silica gelcolumn chromatography to afford1-((S)-3-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)butyl)cyclopropanol ascolorless oil (0.853 g, 74%)².

MS (ESI, pos. ion) m/z: 253.0 (M+23);

¹H NMR (400 MHz, CDCl₃): δ0.4-0.5 (s, 1H), 0.67-0.87 (m, 3H), 1.4-1.9(m, 12H), 3.38-3.44 (m, 1H), 3.53-3.60 (m, 1H), 3.75-3.78 (m, 1H),3.87-3.96 (m, 1H), 4.57 (d, J=2.4 Hz, 1H).

Step 5)(5R)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-oxaspiro[2.4]heptane

To a solution of1-((S)-3-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)butyl)-cyclopropanol(1.73 g, 0.0075 mol) and PPh₃ (2.95 g, 0.0113 mol, Richjoint) in 32 mLof anhydrous THF at rt under N₂ was added DEAD (1.96 g, 0.0113 mol,Aladdin) dropwise via a syringe. The reaction was stirred at 60° C. for12 hours. The solvent was concentrated in vacuo. The red oil waspurified by a silica gel column chromatography (8:1 (v/v)n-hexane/EtOAc) to give the title compound as colorless oil (1.1 g,64%)².

MS (ESI, pos. ion) m/z: 213.0 (M+1);

¹H NMR (400 MHz, CDCl₃): δ 0.4-0.6 (m, 2H), 0.75-0.95 (s, 2H), 1.4-1.9(m, 10H), 3.45-3.52 (m, 2H), 3.73-3.79 (m, 1H), 3.80-3.90 (m, 1H),4.23-4.28 (m, 1H), 4.63-4.69 (s, 1H).

Step 6) (5R)-5-(hydroxymethyl)-4-oxaspiro[2.4]heptane

To a mixture of(5R)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-oxaspiro[2.4]heptane (101mg, 0.48 mmol) in 5 mL of MeOH was added PPTS (12.1 mg, 0.048 mol,Aldrich) at room temperature. The reaction mixture was stirred at 40° C.overnight and then concentrated in vacuo. The residue was purified by asilica gel column chromatography (CH₂Cl₂) to give the title compound ascolorless oil (55 mg, 89%).

¹H NMR (400 MHz, CDCl₃): δ0.4-0.6 (m, 2H), 0.75-0.95 (m, 2H), 1.84-1.91(m, 1H), 1.94-1.98 (m, 2H), 2.07-2.13 (m, 1H), 2.27 (s, 1H), 3.56-3.70(m, 2H), 4.16-4.18 (m, 1H).

Step 7) ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate

To a mixture of (5R)-5-(hydroxymethyl)-4-oxaspiro[2.4]heptane (116 mg,0.9 mmol) and Et₃N-(183.8 mg, 1.82 mmol, Shantou Xilong chemicalfactory) in dry CH₂Cl₂ (6 mL) at −10° C. under N₂, was added MsCl (203mg, 1.4 mmol, Shanghai Haiqu chemical Ltd.) dropwise via a syringe.After stirring for 2 hrs at rt, the reaction was quenched with water ice(3 mL), and the water phases were extracted with CH₂Cl₂ (20 mL×2). Thecombined organic phases were dried over Na₂SO₄, and concentrated invacuo to give ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonateas pale yellow oil.

Step 8)N-(4-(7-(((5R)-4-oxaspiro[2.4]heptane-5-yl)methoxyl)quinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

To a mixture ofN-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide(300 mg, 0.62 mmol) and cesium carbonate (1.0 g, 3.1 mmol, Aladdin) inN,N-dimethylacetamide (1 mL) was added((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate (187.5 mg,0.91 mmol) in 3 mL of N,N-dimethylacetamide. After stirring at 40° C.for 3 days, the reaction mixture was concentrated in vacuo and waschromatographed with a silica gel column (1:6 (v/v) n-hexane/EtOAc) toafford the title compound as a colorless solid (220 mg, 60%).

MS (ESI, pos. ion) m/z: 595.7 (M+1); LC-MS Rt: 4.17 min;

¹H NMR (400 MHz, CDCl₃): δ 0.63 (m, 2H), 0.91 (m, 2H), 2.03 (d, J=5.2Hz, 3H), 2.29 (m, 1H), 2.80 (s, 3H), 3.38 (s, 3H), 4.17 (dd, J₁=16 Hz,J₂=2.4 Hz, 2H), 4.49 (m, 1H), 6.40 (d, J=5.2 Hz, 1H), 7.16 (t, 1H), 7.26(d, J=5.2 Hz, 1H), 7.29 (d, J=2 Hz, 1H), 7.38 (m, 3H), 7.48 (m, 1H),7.56 (t, 2H), 7.90 (dd, J₁=14.8 Hz, J₂=2.4 Hz, 1H), 8.26 (d, J=9.2 Hz,1H), 8.58 (d, J=5.6 Hz, 1H), 10.87 (s, 1H).

Example 3N-(5-(7-(((5R)-4-oxaspiro[2.4]heptane-5-yl)methoxyl)quinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-carboxamide

The title compound was prepared according to the procedure described inExample 2 by usingN-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide(280 mg, 0.69 mmol), cesium carbonate (1.17 g, 3.45 mmol, Aladdin), and((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate (204 mg, 0.99mmol) in DMA (5 mL). The title compound was purified by a silica gelcolumn chromatography (1:8 (v/v) n-hexane/EtOAc) as a colorless solid(110 mg, 27.6%).

MS (ESI, pos. ion) m/z: 578.1 (M+1); LC-MS Rt: 4.11 min;

¹H NMR (400 MHz, CDCl₃): δ0.55 (m, 2H), 0.92 (m, 2H), 2.03 (m, 3H), 2.31(m, 1H), 2.81 (s, 3H), 3.38 (s, 3H), 4.18 (m, 2H), 4.52 (m, 1H), 6.43(d, J=5.6 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.39(m, 3H), 7.51 (m, 4H), 8.23 (t, 1H), 8.38 (d, J=8.8 Hz, 1H), 8.60 (d,J=5.6 Hz, 1H), 11.25 (s, 1H).

Example 4N-(3-fluoro-4-(7-(2-(1-hydroxycyclopropyl)ethoxy)quinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

Step 1) 3-(tetrahydro-2H-pyran-2-yloxy)propanoic acid

To a mixture of 3-hydroxypropanoic acid (7.2 g, 80 mmol, TCI, TOKYOKASEI) and DHP (13.4 g, 160 mmol, Alfa) in dichloromethane (100 mL) andTHF (100 mL) was added PPTS (2 g, 8 mmol, Aldrich) in portions. Thereaction mixture was stirred at rt overnight, and was quenched with 50mL of saturated NaHCO₃ aqueous solution. The resulted mixture wasextracted with dichloromethane (50 mL×5). The combined organic phaseswere dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (1:1 (v/v) petroleumether/EtOAc) to give colorless oil (7.8 g, 56%).

MS (ESI, pos. ion) m/z: 196.9 (M+Na⁺); (ESI, negative. ion) m/z: 172.8(M−1).

Step 2) benzyl 3-(tetrahydro-2H-pyran-2-yloxy)propanoate

To a solution of 3-(tetrahydro-2H-pyran-2-yloxy) propanoic acid (1 g,5.7 mmol) and TEA (0.863 g, 8.55 mmol, Shantou Xilong chemical factory)in 50 mL of CH₂Cl₂ was added BnBr (0.98 g, 5.7 mmol, Aldrich) via asyringe at 0° C. After stirring at rt overnight, the reaction mixturewas quenched with 20 mL of water, and was extracted with ethyl acetate(50 mL×3). The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (20:1 (v/v) petroleum ether/EtOAc) to give the titlecompound as colorless oil (270 mg, 18.6%).

MS (ESI, pos. ion) m/z: 287.0 (M+23);

¹H NMR (400 MHz, CDCl₃): δ1.42-1.79 (m, 6H), 2.65-2.68 (t, 2H),3.48-3.80 (dd, J=12.8 Hz, 2H), 3.71-4.01 (dd, J=12 Hz, 2H), 4.61 (d,1H), 5.15 (s, 2H), 3.71-7.36 (m, 5H).

Step 3) 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)cyclopropanol

To a mixture of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)propanoate (150mg, 0.568 mmol) in 2 mL of THF was added Ti(Oi-Pr)₄ (0.18 mL, 0.568mmol, d=0.955 g/L, Ardrich) via a syringe under nitrogen at rt. Afterstirring at 18° C. for 30 min, EtMgBr (0.48 mL, 1.42 mmol, 3M ethersolution, Aldrich) was added via a syringe pump over 2 hrs. The reactionwas quenched with 5 mL of water, after benzyl3-(tetrahydro-2H-pyran-2-yloxy)propanoate was consumed completely(monitored by TLC). The mixture was filtered through a celite pad andthe filtrate was extracted with ethyl acetate (30 mL×3). The combinedorganic phases were dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by a silica gel column chromatography (10:1 (v/v)petroleum ether/EtOAc) to afford1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)cyclopropanol as colorless oil(60 mg, 57%).

¹H NMR (400 MHz, CDCl₃): δ0.46 (m, 2H), 0.75-0.88 (d, 2H), 1.55-1.83 (m,6H), 1.87-1.90 (m, 2H), 3.55 (q, 1H), 3.69 (q, 1H), 3.88 (t, 1H), 4.06(t, 1H), 4.66 (s, 1H).

Step 4) 1-(2-hydroxyethyl)cyclopropanol

To a mixture of 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)cyclopropanol(380 mg, 2.04 mmol) in 20 mL of methanol was added PPTS (51 mg, 0.204mmol, Aldrich). The reaction mixture was stirred at 40° C. overnight,then treated with 10 mL of water. The resulted mixture was extractedwith dichloromethane (20 mL×3). The combined organic phases were driedover Na₂SO₄ and concentrated in vacuo. The residue was purified by asilica gel column chromatography (10:1 (v/v) petroleum ether/EtOAc) togive the title compound as colorless oil (170 mg, 81.7%).

¹H NMR (400 MHz, CDCl₃): δ0.55 (t, 2H), 0.85 (t, 2H), 1.85 (t, 2H), 4.02(t, 2H).

Step 5) 2-(1-hydroxycyclopropyl)ethyl methanesulfonate

A mixture of 1-(2-hydroxyethyl)cyclopropanol (86 mg, 0.843 mmol) andtriethylamine (136 mg, 1.35 mmol, Shantou Xilong chemical factory) in 10mL of dichloromethane was stirred at −10° C. for 30 min. Methanesulfonylchloride (106 mg, 0.927 mmol, Shanghai Haiqu chemical Ltd.) was thenadded via a syringe. The reaction was stirred at −10° C. for 1 hr at rtand then quenched with 1 mL ice-water. The resulted mixture wasextracted with dichloromethane (20 mL×3). The combined organic phaseswere dried over Na₂SO₄ and concentrated in vacuo to afford2-(1-hydroxycyclopropyl)ethyl methanesulfonate as yellow oil (used inthe next step without further purification).

Step 6)N-(3-fluoro-4-(7-(2-(1-hydroxycyclopropyl)ethoxy)quinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

To a mixture ofN-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide(204 mg, 0.421 mmol) and 2-(1-hydroxycyclopropyl)ethyl methanesulfonate(152 mg, 0.843 mmol) in 8 mL of DMA was added cesium carbonate (1.37 g,4.2 mmol, Aladdin). After stirring at 40° C. for 1 day, the reactionmixture was concentrated in vacuo and the residue was chromatographedwith a silica gel column (50:1 (v/v) CH₂Cl₂/CH₃OH) to afford the titlecompound as a white solid (60 mg, 25%).

MS (ESI, pos. ion) m/z: 569.1 (M+1); LC-MS Rt: 3.948 min;

¹H NMR (400 MHz, CDCl₃): δ0.57 (d, J=8 Hz, 2H), 0.86 (d, J=8 Hz, 2H),2.14 (t, 2H), 2.80 (s, 3H), 3.37 (s, 3H), 4.43 (t, 2H), 6.41 (d, J=4 Hz,1H), 7.14-7.23 (m, 2H), 7.26-7.35 (m, 1H), 7.37-7.38 (m, 2H), 7.45-7.50(m, 2H), 7.50-7.58 (m, 2H), 7.90-7.93 (dd, J=2.4 Hz, 1H), 8.27 (d, J=8Hz, 1H), 8.58 (d, J=8 Hz, 1H), 10.89 (s, 1H).

Example 5 N-(3-fluoro-4-(7-((1-cyclopropylmethanesulfonate-1-yl)methoxyl)quinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

Step 1) ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate

To a mixture of ethyl 2-hydroxyacetate (2 g, 20 mmol, TCI) and3,4-dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL of CH₂Cl₂ was addedPPTS (500 mg, 2 mmol, Aldrich) in portions at rt. The mixture wasstirred at rt for 4 hours. The reaction mixture was then washed withbrine, and the organic layer was separated and the combined organicphases were dried over Na₂SO₄, concentrated in vacuo. The residue waspurified by a silica gel column chromatography (20:1 (v/v) petroleumether/EtOAc) to give the desired compound as colorless oil (3.01 g,81%).

¹H NMR (400 MHz, CDCl₃): δ 1.25-1.32 (m, 3H), 1.55-1.63 (m, 3H),1.69-1.88 (m, 3H), 3.50-3.53 (m, 1H), 3.82-3.88 (m, 1H), 4.18-4.23 (m,4H), 4.73 (t, J=3.2 Hz, 1H).

Step 2) 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol

To a mixture of ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (1 g, 5.3mmol) and Ti(O-iPr)₄ (1.06 mL, 3.5 mmol, Aldrich) in 18 mL of THF underN₂ was added EtMgBr (4.5 mL, 13.25 mmol, 3M ether solution, Aldrich)dropwise over 2 hrs, and the temperature must be kept at 15-20° C. Afterstirring for 2 hrs, and the reaction mixture was quenched with saturatedNH₄Cl aqueous solution at 0° C. and extracted with EtOAc (30 mL×3). Thecombined organic phases were dried over Na₂SO₄ and concentrated invacuo. The residue was purified by a silica gel column chromatography(20:1 (v/v) petroleum ether/EtOAc) to afford1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol as colorless oil(500 mg, 55%).

¹H NMR (400 MHz, CDCl₃): δ 0.51-0.67 (m, 2H), 0.77-0.85 (m, 2H),1.55-1.65 (m, 4H), 1.74-1.87 (m, 2H), 3.50-3.55 (m, 2H), 3.81 (d, J=11.6Hz, 1H), 3.93-3.98 (m, 2H), 4.64-4.66 (m, 1H).

Step 3) 1-(hydroxymethyl)cyclopropanol

To a mixture of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol(420 mg, 2.44 mmol) in 30 mL of MeOH was added PPTS (61 mg, 0.244 mmol,Aldrich) at rt. The reaction mixture was stirred at rt overnight, andthen concentrated and purified by a silica gel column chromatography(1:2 (v/v) petroleum ether/EtOAc) to afford1-(hydroxymethyl)-cyclopropanol as colorless oil (209 mg, 99%).

¹H NMR (400 MHz, CDCl₃): δ 0.56 (t, J=5.6 Hz, 2H), 0.82 (t, J=6 Hz, 2H),3.62 (s, 2H).

Step 4) (1-(methylsulfonyloxy)cyclopropyl)methyl methanesulfonate

To a mixture of 1-(hydroxymethyl)cyclopropanol (100 mg, 1.14 mmol) andTEA (202 mg, 1.82 mmol, Shantou Xilong chemical factory) in 20 mL of dryCH₂Cl₂ under N₂, was added MsCl (156 mg, 1.32 mmol, Shanghai Haiquchemical Ltd.) dropwise via a syringe at −10° C. After stirring for 4hrs at −10° C., the mixture was washed with ice-water and extracted withCH₂Cl₂ (30 mL×3). The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo to give the desired compound as pale yellow oil(139 mg, 50%).

Step 5) N-(3-fluoro-4-(7-((1-cyclopropylmethanesulfonate-1-yl)methoxyl)quinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

To a mixture of (1-(methylsulfonyloxy)cyclopropyl)methylmethanesulfonate (122 mg, 0.5 mmol) andN-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-2,5-dihydro-2,3-dimethyl-5-oxo-1-phenyl-1H-pyrazole-4-carboxamide(306 mg, 0.57 mmol) in 3 mL of DMA under N₂ was added Cs₂CO₃ (926 mg,2.84 mmol, Aladdin) at rt. The mixture was stirred at rt overnight, andthen was concentrated in vacuo. The residue was purified by a silica gelcolumn chromatography (5:1 (v/v) CH₂Cl₂/EtOAc) to give the titlecompound as a white solid (200 mg, 55%).

MS (ESI, pos. ion) m/z: 633.1 (M+1); LC-MS Rt: 4.178 min;

¹H NMR (400 MHz, CDCl₃): δ 1.09 (t, J=7.2 Hz, 2H), 1.54 (t, J=6.8 Hz,2H), 2.80 (s, 3H), 3.07 (s, 3H), 3.38 (s, 3H), 4.45 (s, 2H), 6.43 (d,J=4.2 Hz, 2H), 7.17 (t, J=8.8 Hz, 1H), 7.27-7.32 (m, 2H), 7.36-7.40 (dd,J=0.2 Hz, 3H), 7.49 (d, J=7.2 Hz, 1H), 7.57 (t, J=8 Hz, 2H), 7.90-7.94(dd, J=2.4 Hz, 1H), 8.31 (d, J=4.2 Hz, 1H), 8.60 (d, J=4.2 Hz, 1H).

Example 6N-(4-(7-(4-oxaspiro[2.4]heptane-6-yloxy)-6-methoxyl-quinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

Step 1)4-(tetrahydro-2H-pyran-2-yloxy)-dihydrofuran-2(3H)-one

To a mixture of 4-hydroxy-dihydrofuran-2(3H)-one (10 g, 0.1 mol, Alfa)and dihydropyran (12.5 g, 0.15 mol, Alfa) in 250 mL of dry CH₂Cl₂ wasadded PPTS (2.5 g 0.01 mol), and the reaction mixture was stirred at rtovernight. The reaction mixture was washed with brine and extracted withCH₂Cl₂ (100 mL×3), and the combined organic phases were dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by a silicagel column chromatography (3:1 (v/v) EtOAc/n-Hexane) to give the titlecompound as colorless oil (15.6 g, 68%).

¹H NMR (400 MHz, CDCl₃): δ 1.63-1.84 (m, 6H), 2.54-2.79 (m, 2H),3.52-3.55 (dd, J=12 Hz, 1H), 3.79-3.86 (m, 1H), 4.31-4.47 (m, 2H),4.57-4.59 (t, J=4 Hz, 2H).

Step 2) 1-(3-hydroxy-2-(tetrahydro-2H-pyran-2-yloxy)propyl)cyclopropanol

To a solution of 4-(tetrahydro-2H-pyran-2-yloxy)-dihydrofuran-2(3H)-one(2.23 g, 12 mmol) and Ti(Oi-Pr)₄ (0.68 g, 2.4 mmol, Aldrich) in 40 mL ofdry THF at 15° C. under N₂ was added EtMgBr (30 mmol, 10 mL, 3M ethersolution, Aldrich) dropwise via a syringe pump over 2 hrs. Thetemperature of the reaction was always kept below 20° C. After stirringfor 2 hrs, the reaction mixture was quenched with 30 mL of saturatedNH₄Cl aqueous solution, and was extracted with ethyl acetate (50 mL×3).The combined organic phases were dried over Na₂SO₄ and concentrated invacuo. The residue was purified by a silica gel column chromatography(1:1 (v/v) EtOAc/n-hexane) to afford1-(3-hydroxy-2-(tetrahydro-2H-pyran-2-yloxy)propyl)cyclopropanol asyellow oil (1.92 g, 73%).²

¹H NMR (400 MHz, CDCl₃): δ 0.40-0.53 (m, 2H), 0.71-0.83 (m, 2H),1.53-1.67 (m, 5H), 1.81-1.96 (m, 3H), 3.49-3.72 (m, 3H), 3.98-4.11 (m,2H), 4.64-4.73 (m, 1H).

Step 3) 3-(1-hydroxycyclopropyl)-2-(tetrahydro-2H-pyran-2-yloxy)propylmethanesulfonate

To a mixture of1-(3-hydroxy-2-(tetrahydro-2H-pyran-2-yloxy)propyl)cyclopropanol (1.0 g,4.63 mmol) and triethylamine (1 mL, 7.4 mmol, Shantou Xilong chemicalfactory) in 30 mL of CH₂Cl₂ at 0° C. was added methanesulfonyl chloride(0.64 g, 5.6 mmol, Shanghai Haiqu chemical Ltd.) via a syringe. Thereaction mixture was stirred at 0° C. for 1 hr and then quenched with 5mL of ice-water. The resulted mixture was extracted with CH₂Cl₂ (50mL×3). The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo to furnish3-(1-hydroxycyclopropyl)-2-(tetrahydro-2H-pyran-2-yloxy)propylmethanesulfonate as yellow oil (used in the next step immediatelywithout further purification).

Step 4) 6-(tetrahydro-2H-pyran-2-yloxy)-4-oxaspiro[2.4]heptane

A mixture of3-(1-hydroxycyclopropyl)-2-(tetrahydro-2H-pyran-2-yloxy)propylmethanesulfonate (1.3 g, 4.63 mmol) and NaH (0.15 g, 6 mmol, Aldrich) in20 mL of THF was stirred at rt for 4 hrs. The reaction mixture wasquenched with 5 mL of methanol. The mixture was diluted with 10 mL ofwater and extracted with ethyl acetate (30 mL×3). The combined organicphases were dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by a silica gel column chromatography (1:10 (v/v)EtOAc/petrolum ether) to give the title compound as colorless oil (380mg, 42%).

¹H NMR (400 MHz, CDCl₃): δ 0.45-0.63 (dd, J=4.8 Hz, 2H), 0.81-0.93 (dd,J=4.8 Hz, 2H), 1.56-2.29 (m, 8H), 3.54 (s, 1H), 3.87-4.03 (m, 3H),4.60-4.66 (m, 2H).

Step 5) 6-hydroxy-4-oxaspiro[2.4]heptane

A mixture of 6-(tetrahydro-2H-pyran-2-yloxy)-4-oxaspiro[2.4]heptane(1.03 g, 5.2 mmol) and PPTS (0.26 g, 1.0 mmol, Aldrich) in methanol (40ml) was stirred at 40° C. for 5 hrs. The reaction mixture wasconcentrated in vacuo, and the residue was purified by a silica gelcolumn chromatography (1:5 (v/v) EtOAc/petroleum ether) to afford6-hydroxy-4-oxaspiro[2.4]heptane as colorless oil (570 mg, 97%).

¹H NMR (400 MHz, CDCl₃): δ 0.47-0.65 (m, 2H), 0.81-0.96 (m, 2H),1.89-2.35 (m, 2H), 3.80-3.96 (m, 2H), 4.59 (s, 1H)

Step 6) (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate

To a mixture of 6-hydroxy-4-oxaspiro[2.4]heptane (100 mg, 0.88 mmol) andtriethylamine (150 mg, 1.5 mmol, Shantou Xilong chemical factory) in 5mL of dichloromethane at 0° C. was added methanesulfonyl chloride (130mg, 1 mmol, Shanghai Haiqu chemical Ltd.) via a syringe. The reactionmixture was stirred at 0° C. for 1 hr and was quenched with 5 mL ofice-water. The resulted mixture was extracted with CH₂Cl₂ (20 mL×3). Thecombined organic phases were dried over Na₂SO₄ and concentrated in vacuoto give the title compound as yellow oil (168 mg, 100%).

Step 7)N-(4-(7-(4-oxaspiro[2.4]heptane-6-yloxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

To a mixture of (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (168 mg,0.877 mmol) andN-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide(300 mg, 0.584 mmol) in 5 mL of N,N-dimethylacetamide was added cesiumcarbonate (893 mg, 2.74 mmol, Aladdin). After stirring at rt for 4 hrs,the reaction was warmed to 40° C. and stirred for 16 hrs. The reactionmixture was concentrated in vacuo and chromatographed with a silica gelcolumn (5:1 (v/v) EtOAc/n-hexane) to afford the title compound as awhite solid (65 mg, 18%).

MS (ESI, pos. ion) m/z: 611.1 [M+1]; LC-MS Rt: 4.10 min;

¹H NMR (400 MHz, CDCl₃): δ 0.56-0.71 (m, 2H), 0.81-1.02 (m, 2H), 2.33(m, 1H), 2.55 (m, 1H), 2.81 (s, 3H), 3.38 (s, 3H), 4.03 (s, 3H), 4.21(m, 2H), 5.24 (t, J=4 Hz, 1H), 6.43 (d, J=4 Hz, 1H), 7.15-7.60 (m, 9H),7.90-7.94 (m, 1H), 8.48 (d, J=4 Hz, 1H), 10.89 (s, 1H).

Example 7N-(4-(7-(4-oxaspiro[2.4]heptane-6-yloxy)quinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

The title compound was prepared according to the procedure described inExample 6 by using (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (220mg, 1.14 mmol),N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide(300 mg, 0.62 mmol), and cesium carbonate (450 mg, 2.4 mmol, Aladdin) inDMA (6 mL). The title compound was purified by a silica gel columnchromatography (5:1 (v/v) EtOAc/n-hexane) and was obtained as a whitesolid (68 mg, 19%).

MS (ESI, pos. ion) m/z: 581.1 [M+1]; LC-MS Rt: 4.255 min;

¹H NMR (400 MHz, CDCl₃): δ 0.54-0.72 (m, 2H), 0.88-1.07 (m, 2H), 2.29(m, 1H), 2.57 (m, 1H), 2.84 (s, 3H), 3.42 (s, 3H), 4.22 (m, 2H), 5.26(m, 1H), 6.46 (d, J=4 Hz, 1H), 7.18-7.63 (m, 9H), 7.96 (m, 1H), 8.33 (d,J=8 Hz, 1H), 8.62 (d, J=4 Hz, 1H), 10.92 (s, 1H).

Example 8N-(5-(7-(4-oxaspiro[2.4]heptane-6-yloxy)quinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

The title compound was prepared according to the procedure described inExample 6 by using (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (220mg, 1.14 mmol),N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide(300 mg, 0.64 mmol), and cesium carbonate (450 mg, 2.4 mmol, Aladdin) inDMA (6 mL). The title compound was purified with a silica gel columnchromatography (EtOAc) to give a white solid (140 mg, 39%).

MS (ESI, pos. ion) m/z: 564.1 [M+1]; LC-MS Rt: 4.007 min;

¹H NMR (400 MHz, CDCl₃): δ 0.59 (m, 2H), 0.91 (m, 2H), 2.25 (d, J=14 Hz,1H), 2.53 (m, 1H), 2.80 (s, 3H), 3.37 (s, 3H), 4.18 (m, 2H), 5.22 (t,J=4 Hz, 1H), 6.44 (d, J=5 Hz, 1H), 7.24-7.56 (m, 9H), 8.25 (m, 1H), 8.38(d, J=9 Hz, 1H), 8.60 (d, J=3 Hz, 1H), 11.26 (s, 1H).

Example 9N-(3-fluoro-4-(7-(3-(1-hydroxycyclopropyl)propoxy)quinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

Step 1) 1-(3-hydroxypropyl)cyclopropanol

To a mixture of dihydrofuran-2(3H)-one (2.0 g, 23 mmol, Alfa) andTi(Oi-Pr)₄ (1.32 g, 4.6 mmol, Aldrich) in 80 mL of dry THF at 15° C.under N₂ was added EtMgBr (60 mmol, 20 mL, 3M in ether solution,Aldrich) via a syringe pump over 3 hrs. The temperature was always keptbelow 20° C. After stirring for additional 3 hrs, the reaction mixturewas quenched with 60 mL of saturated NH₄Cl aqueous solution, and wasextracted with ethyl acetate (50 mL×3). The combined organic phases weredried over Na₂SO₄ and concentrated in vacuo. The orange oil residue waspurified by a silica gel column chromatography (1:1 (v/v)EtOAc/n-Hexane) to afford 1-(3-hydroxypropyl)cyclopropanol as yellow oil(2.5 g, 93%).

Step 2) 3-(1-hydroxycyclopropyl)propyl methanesulfonate

A mixture of 1-(3-hydroxypropyl)cyclopropanol (140 mg, 1.2 mmol) andtriethylamine (0.3 mL, 2.1 mmol, Shantou Xilong chemical factory) in 8mL of dichloromethane was stirred at 0° C. for 10 min. To the mixturewas added methanesulfonyl chloride (180 mg, 1.6 mmol, Shanghai Haiquchemical Ltd.) via a syringe. The reaction mixture was stirred at 0° C.for 1 hr and then quenched with 2 mL of ice-water. The resulted mixturewas extracted with dichloromethane (10 mL×3). The combined organicphases were dried over Na₂SO₄ and concentrated in vacuo to give3-(1-hydroxycyclopropyl) propyl methanesulfonate as yellow oil.

Step 3)N-(3-fluoro-4-(7-(3-(1-hydroxycyclopropyl)propoxy)quinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

To a mixture of 3-(1-hydroxycyclopropyl)propyl methanesulfonate (240 mg,1.2 mmol) andN-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide(300 mg, 0.62 mmol) in 5 mL of N,N-dimethylacetamide was added cesiumcarbonate (470 mg, 2.4 mmol, Aladdin). After stirring at rt for 12 hrs,the reaction mixture was warmed to 40° C. and stirred for additional 6hrs. The reaction mixture was diluted with 20 mL of water and extractedwith ethyl acetate (40 mL×3). The combined organic phases were driedover Na₂SO₄, concentrated in vacuo and chromatographed with a silica gelcolumn (5:1 (v/v) EtOAc/n-Hexane) to provide the title compound as awhite solid (68 mg, 19%).

MS (ESI, pos. ion) m/z: 583.1 [M+1]; LC-MS Rt: 4.129 min;

¹H NMR (400 MHz, CDCl₃): δ 0.51 (m, 2H), 0.79 (m, 2H), 1.81 (t, J=8 Hz,2H), 2.15 (m, 2H), 2.81 (s, 3H), 3.38 (s, 3H), 4.24 (t, J=8 Hz, 2H),6.41 (d, J=4 Hz, 1H), 7.15-7.59 (m, 9H), 7.91 (m, 1H), 8.27 (d, J=8 Hz,1H), 8.58 (d, J=4 Hz, 1H), 10.87 (s, 1H).

N-(3-fluoro-4-(7-(3-(1-cyclopropyl-methanesulfonate-1-yl)propoxy)-quinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamidewas also isolated from the above reaction:

MS (ESI, pos. ion) m/z: 661.1 [M+1]; LC-MS Rt: 4.272 min;

¹H NMR (400 MHz, CDCl₃): δ 0.787 (m, 2H), 1.29 (m, 2H), 2.11 (m, 4H),2.80 (s, 3H), 3.01 (s, 3H), 3.38 (s, 3H), 4.22 (t, J=6 Hz, 2H), 6.41 (d,J=5 Hz, 1H), 7.14-7.59 (m, 9H), 7.91 (m, 1H), 8.27 (d, J=9 Hz, 1H), 8.58(d, J=5 Hz, 1H), 10.88 (s, 1H).

Example 10 N-(5 (7 (3 (1hydroxycyclopropyl)propoxy)quinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

The title compound was prepared according to the procedure described inExample 9 by usingN-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide(277 mg, 0.593 mmol), Cs₂CO₃ (560 mg, 1.724 mmol, Aladdin), and3-(1-hydroxycyclopropyl)propyl methanesulfonate (334 mg, 1.724 mmol) inDMA (10 mL). The title compound was purified by a silica gel columnchromatography (67:30:1:2 (v/v/v/v) EtOAc/CH₂Cl₂/CH₃OH/Et₃N) to affordthe title compound as a white solid (210 mg, 62.6%).

MS (ESI, pos. ion) m/z: 566 [M+1]; LC-MS Rt: 3.846 min;

¹H NMR (400 MHz, CDCl₃): δ 0.49-052 (t, J=6 Hz, 2H), 0.78-0.81 (t, J=6Hz, 2H), 1.26 (s, 2H), 1.79-1.83 (t, J=7.2 Hz, 2H), 2.13-2.16 (t, J=7.2Hz, 2H), 2.81 (s, 3H), 3.38 (s, 3H), 4.23-4.26 (t, J=6 Hz, 2H),6.42-6.44 (d, J=5.2 Hz, 1H), 7.20-7.23 (q, J₁=9.2 Hz, J₂=2.4 Hz, 1H),7.37-7.39 (d, J=7.6 Hz, 1H), 7.42 (s, 1H), 7.44-7.57 (m, 4H), 8.22-8.25(m, 2H), 8.37-8.39 (d, J=9.2 Hz, 1H), 8.59-8.60 (d, J=5.2 Hz, 1H), 11.26(s, 1H).

Example 11N-(5-(7-((4-oxaspiro[2.4]heptane-6-yl)aminopropoxy)quinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

Step 1) (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate

To a solution of 6-hydroxy-4-oxaspiro[2.4]heptane (200 mg, 1.75 mmol)and Et₃N-(530.25 mg, 5.25 mmol) in dry CH₂Cl₂ (8 mL) at −10° C. wasadded MsCl (401.7 mg, 3.5 mmol) dropwise under N₂ atmosphere. Afterstirring for 2 hrs, the reaction was quenched with ice-water (3 mL),extracted with CH₂Cl₂ (2×10 mL). The combined organic phases were driedover Na₂SO₄, concentrated in vacuo to give the title compound as paleyellow oil.

Step 2) (4-oxaspiro[2.4]heptane-6-yl)aminopropanol

To a solution of (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (336 mg,1.75 mmol) in dry THF (3 mL) was added 3-aminopropan-1-ol (656.3 mg,8.75 mmol, TCI). The reaction was refluxed overnight. The mixture wasconcentrated in vacuo to give a brown residue, which was chromatographedwith a silica gel column (8:1 (v/v) EtOAc/MeOH) to give the titlecompound as pale yellow oil (280 mg, 93%).

MS (ESI, pos. ion) m/z: 171.0 (M+1).

¹H NMR (400 MHz, CDCl₃): δ 0.45 (m, 1H), 0.54 (m, 1H), 0.88 (m, 2H),1.75 (m, 2H), 1.83 (dd, J₁=4 Hz, J₂=16.8 Hz, 1H), 2.22 (dd, J₁=7.2 Hz,J₂=20 Hz, 1H), 2.40 (s, 2H), 3.58 (m, 1H), 3.72 (m, 1H), 3.83 (t, 2H),3.96 (dd, J₁=14.8 Hz, J₂=5.6 Hz, 1H).

Step 3) tert-butyl N-(4-oxaspiro[2.4]heptane-6-yl)hydroxypropylaminoformate

To a solution of (4-oxaspiro[2.4]heptane-6-yl)aminopropanol (361.9 mg,2.12 mmol) and Et₃N-(535.3 mg, 5.3 mmol) in CH₂Cl₂ (10 mL) at roomtemperature was added (Boc)₂O (692 mg, 3.17 mmol). The reaction wasstirred overnight and was then quenched with water (5 mL). The organiclayer was separated and the water layer was extracted with 20 mL ofEtOAc. The combined organic phases were dried over Na₂SO₄, concentratedin vacuo to give the title compound as pale yellow oil (555.8 mg, 97%).

MS (ESI, pos. ion) m/z: 272.0 (M+1);

¹H NMR (400 MHz, CDCl₃): δ 0.45 (m, 1H), 0.61 (m, 1H), 0.78 (m, 1H),0.93 (m, 1H), 1.47 (s, 9H), 1.75 (m, 3H), 2.13 (t, 2H), 3.42 (s, 2H),3.59 (d, J=5.2 Hz, 2H), 3.76 (dd, J₁=5.6 Hz, J₂=14.8 Hz, 1H), 3.94 (dd,J₁=7.6 Hz, J₂=16.4 Hz, 1H), 4.71 (s, 1H).

Step 4) (N-(4-oxaspiro[2.4]heptane-6-yl)-tert butoxycarbonylamino)propylmethanesulfonate

To a solution of tert-butylN-(4-oxaspiro[2.4]heptane-6-yl)hydroxypropylamino formate (278 mg, 1.03mmol) and Et₃N-(260 mg, 2.58 mmol) in dry CH₂Cl₂ (10 mL) at −10° C. wasadded MsCl (234.8 mg, 2.06 mmol) dropwise under N₂ atmosphere. Afterstirring for 2 hrs, the reaction was quenched with ice water (3 mL). Theorganic phase was separated and the water layer was extracted with 15 mLof CH₂Cl₂. The combined organic phases were dried over Na₂SO₄,concentrated in vacuo to give the title compound as pale yellow oil.

Step 5) N-(5-(7-((N-(4-oxaspiro[2.4]heptane-6-yl)-tertbutoxycarbonylamino)propoxy)quinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

To a solution ofN-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide(200.6 mg, 0.44 mmol) and cesium carbonate (684.6 mg, 2.1 mmol, Aladdin)in N,N-dimethylacetamide (1 mL) was added(N-(4-oxaspiro[2.4]heptane-6-yl)-tert butoxycarbonylamino)propylmethanesulfonate (0.63 mmol) in N,N-dimethylacetamide (5 mL). Afterstirring at 40° C. for 2 days, the reaction mixture was concentrated invacuo. The residue was chromatographed with a silica gel column (1:4(v/v) n-hexane/EtOAc) to give the title compound as a white solid (200mg, 62.5%).

MS (ESI, pos. ion) m/z: 721.2 (M+1); LC-MS Rt: 4.669 min;

¹H NMR (400 MHz, CDCl₃): δ 0.55 (m, 1H), 0.65 (m, 1H), 0.78 (m, 1H),0.93 (m, 1H), 1.49 (s, 9H), 2.09 (m, 2H), 2.18 (m, 3H), 2.81 (s, 3H),3.38 (s, 3H), 3.45 (m, 2H), 3.78 (dd, J₁=5.6 Hz, J₂=14.8 Hz, 1H), 3.95(m, 1H), 4.16 (t, 2H), 6.43 (d, J=5.6 Hz, 1H), 7.22 (dd, J₁=2.4 Hz,J₂=11.6 Hz, 1H), 7.38 (m, 3H), 7.51 (m, 4H), 8.23 (d, J=4.4 Hz, 1H),8.24 (d, J=2 Hz, 1H), 8.38 (d, J=9.2 Hz, 1H), 8.60 (d, J=5.2 Hz, 1H),11.26 (s, 1H).

Step 6)N-(5-(7-((4-oxaspiro[2.4]heptane-6-yl)aminopropoxy)quinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

To a solution of N-(5-(7-((N-(4-oxaspiro[2.4]heptane-6-yl)-tertbutoxycarbonylamino)propoxy)quinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide(50 mg, 0.069 mmol) in dry THF (2 mL) was added 2 M HCl/THF (8 mmol).After stirring at room temperature for 4 hrs, 10 mL of saturated NaHCO₃aqueous solution was added to quench the reaction. The mixture wasextracted with EtOAc (15 mL×2). The combined organic phases were driedover Na₂SO₄, concentrated in vacuo. The crude product waschromatographed with a silica gel column (5:1 (v/v) EtOAc/MeOH) to givethe title compound as a white solid (30 mg, 69%).

MS (ESI, pos. ion) m/z: 621.2 (M+1); LC-MS Rt: 3.192 min;

¹H NMR (400 MHz, CDCl₃): δ 0.48 (m, 1H), 0.57 (m, 1H), 0.81 (m, 1H),0.89 (m, 1H), 1.94 (dd, J₁=4 Hz, J₂=12 Hz, 1H), 2.12 (m, 2H), 2.24 (dd,J₁=7.2 Hz, J₂=20 Hz, 1H), 2.81 (s, 3H), 2.91 (t, 2H), 3.38 (s, 3H), 3.63(d, J=6.4 Hz, 1H), 3.75 (dd, J₁=3.6 Hz, J₂=12.4 Hz, 1H), 4.00 (dd,J₁=6.0 Hz, J₂=14.8 Hz, 1H), 4.24 (t, 2H), 6.43 (d, J=5.2 Hz, 1H), 7.22(dd, J=2.4 Hz, J=11.6 Hz, 1H), 7.38 (m, 3H), 7.51 (m, 4H), 8.23 (d,J=2.8 Hz, 1H), 8.24 (d, J=3.6 Hz, 1H), 8.38 (d, J=8.8 Hz, 1H), 8.60 (d,J=5.2 Hz, 1H), 11.26 (s, 1H).

Example 12N-(5-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)quinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

Step 1) ethyl 1-acetylcyclopropanecarboxylate

To a solution of ethyl 3-oxobutanoate (26 g, 200 mmol) in acetone (500mL) was added potassium carbonate (82.8 g, 600 mmol) followed by1,2-dibromoethane (45.12 g, 240 mmol). The reaction was refluxed for 24hrs, then the reaction mixture was filtered. The filtrate wasconcentrated in vacuo, and the residue was purified by a silica gelcolumn chromatography (1:50(v/v)EtOAc/n-hexane) to afford the titlecompound as colorless oil (18.7 g, 60%).

MS (ESI, pos. ion) m/z: 157 (M+1);

¹H NMR (400 MHz, CDCl₃): δ 1.25-1.29 (t, J=7.2 Hz, 3H), 1.45 (s, 4H),2.45 (s, 3H), 4.18-4.20 (q, 2H).

Step 2) ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate

To a 100 mL of round-bottomed flask was added ethyl1-acetylcyclo-propanecarboxylate (15.6 g, 100 mmol) and NBS solid (21.36g, 120 mmol), followed by p-toluene sulfonic acid (1.9 g, 10 mmol).After stirring at rt for 8 hrs, the reaction mixture was extracted withdiethyl ether (200 mL) and washed with 80 mL of water. The organic phasewas then dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by a silica gel column chromatography(1:30(v/v)EtOAc/n-hexane) to give the title compound as colorless oil(16.68 g, 71%).

MS (ESI, pos. ion) m/z: 235, 237 (M+1);

¹H NMR (400 MHz, CDCl₃): δ 1.27 (t, J=7.2 Hz, 3H), 1.59-1.64 (m, 4H),4.19-4.24 (q, J₁=14.4 Hz, J₂=7.2 Hz, 2H), 4.49 (s, 2H).

Step 3) 5-((R)-α-methylbenzyl)-4,7-dioxo-5-azaspiro[2.4]heptane

To a solution of ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate (4.7 g,20 mmol) in THF (60 mL) was added (R)-α-methylbenzylamine (2.9 g, 24mmol) and Et₃N (4.04 g, 40 mmol). After stirring at rt for 3 days, thereaction mixture was concentrated in vacuo, and the residue wasextracted with ethyl acetate (50 mL×2) and washed with water (30 mL).The combined organic phases were dried over anhydrous Na₂SO₄, filteredand the filtrate was concentrated in vacuo. The residue was purified bya silica gel column chromatography (EtOAc) to afford the title compoundas a light yellow solid (3.66 g, 80%).

MS (ESI, pos. ion) m/z: 230 (M+1);

¹H NMR (400 MHz, CDCl₃): δ 1.58-1.60 (m, 4H), 1.62-1.63 (d, J=5.6 Hz,3H), 3.49-3.53 (d, J=17.6 Hz, 1H), 3.83-3.88 (d, J=17.6 Hz, 1H),5.80-5.82 (q, 1H), 7.26-7.39 (m, 5H).

Step 4) 5-((R)-α-methylbenzyl)-7-hydroxy-5-azaspiro[2.4]heptane

To a suspension of LiAlH₄ (0.995 g, 26.2 mmol) in THF (40 mL) was addeda solution of 5-((R)-α-methylbenzyl)-4,7-dioxo-5-azaspiro[2.4]heptane(3.0 g, 13.1 mmol) in THF (10 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 2 hrs, then warmed up to 50° C. and continued tostir for 6 hrs. The reaction mixture was then cooled to 0° C. and ethylacetate (10 mL) and water (10 mL) were added. The suspension wasfiltered and the filtrate was concentrated in vacuo. The residue waspurified by a silica gel column chromatography (1:3 (v/v)2-butanol/n-hexane) to afford the title compound as colorless oil (2.4g, 85%).

MS (ESI, pos. ion) m/z: 218 (M+1);

Step 5) 7-hydroxy-5-azaspiro[2.4]heptane

To a solution of 5-((R)-α-methylbenzyl)-7-hydroxy-5-azaspiro[2.4]heptane(2.4 g, 11.1 mmol) in ethanol (30 mL) was added the catalytic amount ofPd/C. The suspension was then stirred under H₂ for 3 hrs. The suspensionwas filtered and the filtrate was concentrated in vacuo to afford thedesired compound as light orange oil (1.23 g, 98%). The crude productwas used for the next step without further purification.

MS (ESI, pos. ion) m/z: 114 (M+1);

Step 6) 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propanol

To a solution of 7-hydroxy-5-azaspiro[2.4]heptane (1.23 g, 11.0 mmol) inTHF (40 mL) was added 3-bromopropanol (2.3 g, 16.65 mmol) and Et₃N-(2.24g, 22.2 mmol). The reaction mixture was stirred at rt for 12 hrs andthen concentrated in vacuo. The residue was purified by a silica gelcolumn chromatography (100:50:2(v/v/v)EtOAc/CH₃OH/Et₃N) to afford thedesired compound as orange oil (1.14 g, 60%).

MS (ESI, pos. ion) m/z: 172 (M+1); LC-MS Rt: 0.178 min;

¹H NMR (400 MHz, CDCl₃): δ 0.59 (m, 1H), 0.62 (m, 1H), 0.70-0.72 (m,1H), 0.87-0.92 (m, 1H), 1.68-1.74 (m, 2H), 2.39-2.41 (d, J=9.2 Hz, 1H),2.70-2.74 (m, 2H), 2.84-2.87 (m, 2H), 2.88-2.92 (dd, J₁=10.4 Hz, J₂=4.8Hz, 1H), 3.73-3.75 (m, 1H), 3.77-3.80 (t, J=5.2 Hz, 2H);

Step 7) 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate

To a solution of 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propanol (1.14g, 6.67 mmol) and Et₃N-(1.35 g, 13.34 mmol) in CH₂Cl₂ (20 mL) was addedmethanesulfonyl chloride (1.15 g, 10 mmol) dropwise at 0° C. Thereaction was then stirred at 0° C. for 3 hrs. The reaction mixture waswashed with cold water (10 mL) and the organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to afford the titlecompound as orange oil. The crude product was used for the next stepwithout further purification.

Step 8) N-(5 (7 (3 (7hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)quinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

To a solution ofN-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide(300 mg, 0.642 mmol) in DMA (3 mL) was added3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (240mg, 0.963 mmol) and Cs₂CO₃ (417 mg, 1.284 mmol). The reaction wasstirred at rt for 24 hrs. The solvent was removed and the residue waspartioned between saturated NaHCO₃ aqueous solution (15 mL) and CHCl₃(30 mL). The organic layer was separated, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by a silicagel column chromatography (100:15:1(v/v/v)EtOAc/CH₃OH/Et₃N) to affordthe title compound as a white solid (259 mg, 65%).

MS (ESI, pos. ion) m/z: 621(M+1); LC-MS Rt: 3.209 min;

¹H NMR (400 MHz, CDCl₃): δ 0.63 (m, 1H), 0.67 (m, 1H), 0.76-0.79 (m,1H), 0.96-0.99 (m, 1H), 2.11-2.14 (m, 2H), 2.47-2.50 (d, J=8.4 Hz, 1H),2.80 (s, 3H), 3.00-3.03 (d, J=9.6 Hz, 1H), 3.06-3.08 (d, J=10.4 Hz, 1H),3.37 (s, 5H), 3.76-3.77 (d, J=3.6 Hz, 1H), 4.23-4.24 (m, 2H), 6.42-6.43(d, J=5.2 Hz, 1H), 7.20-7.23 (d, J=8.8 Hz, 1H), 7.36-7.38 (d, J=7.6 Hz,2H), 7.47-7.49 (m, 5H), 7.53-7.57 (m, 2H), 8.22-8.24 (d, J=8.4 Hz, 2H),8.37-8.39 (d, J=9.2 Hz, 1H), 8.58-8.59 (d, J=4.8 Hz, 1H), 11.25 (s, 1H)

Example 13

N-(4-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)quinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide

To a solution ofN-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide(240 mg, 0.525 mmol) in DMA (3 mL) was added3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (261mg, 1.05 mmol) and Cs₂CO₃ (512 mg, 1.575 mmol). The reaction was thenstirred at rt for 24 hrs. The solvent was removed and the residue waspartioned between saturated NaHCO₃ (10 mL) aqueous solution and CHCl₃(30 mL). The organic layer was separated, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by a silicagel column chromatography (100:15:1(v/v/v)EtOAc/CH₃OH/Et₃N) to affordthe desired compound as a white solid (170 mg, 53%).

MS (ESI, pos. ion) m/z: 611 (M+1);

¹H NMR (400 MHz, CDCl₃): δ 0.59-0.60 (m, 1H), 0.62-0.65 (m, 1H),0.73-0.78 (m, 1H), 0.92-0.96 (m, 1H), 1.58-1.62 (q, J₁=8.0 Hz, J₂=4.4Hz, 2H), 1.81-1.84 (m, 2H), 2.05-2.88 (m, 2H), 2.38-2.40 (d, J=8.4 Hz,1H), 2.68-2.73 (m, 2H), 2.81-2.85 (dd, J₁=4.8 Hz, J₂=4.4 Hz, 1H),2.90-2.92 (d, J=8.8 Hz, 1H), 2.96-2.98 (d, J=9.2 Hz, 1H), 3.74-3.73 (d,J=3.6 Hz, 1H), 4.21-4.26 (m, 2H), 6.36-6.38 (d, J=5.2 Hz, 1H), 7.18-7.24(m, 2H), 7.26-7.29 (d, J=10.4 Hz, 1H), 7.36-7.40 (t, J=8 Hz, 2H),7.48-7.51 (m, 2H), 7.75-7.79 (dd, J₁=2 Hz, J₂=2.4 Hz, 1H), 8.05 (s, 1H),8.24-8.26 (d, J=9.2 Hz, 1H), 8.56-8.58 (d, J=5.2 Hz, 1H), 10.19 (s, 1H).

Example 14N-(4-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)quinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

To a solution ofN-(3-fluoro-4-(7-hydroxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide(200 mg, 0.413 mmol) in DMA (3 mL) was added3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (154mg, 0.619 mmol) and Cs₂CO₃ (268 mg, 0.826 mmol). The reaction was thenstirred at rt for 40 hrs. The solvent was removed and the residue waspartioned between saturated NaHCO₃ aqueous solution (10 mL) and CHCl₃(25 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (100:15:1(v/v/v)EtOAc/CH₃OH/Et₃N) to afford a pale yellowsolid (192 mg, 73%).

MS (ESI, pos. ion) m/z: 638 (M+1); LC-MS Rt: 3.140 min;

¹H NMR (400 MHz, CDCl₃): δ 0.63-0.65 (m, 1H), 0.67-0.69 (m, 1H),0.76-0.81 (m, 1H), 0.98-1.02 (m, 1H), 2.08-2.17 (m, 2H), 2.54-2.57 (d,J=9.2 Hz, 1H), 2.80 (s, 3H), 2.81 (m, 2H), 2.98-3.02 (dd, J₁=4.8 Hz,J₂=4.4 Hz, 1H), 3.08-3.10 (d, J=9.2 Hz, 1H), 3.12-3.14 (d, J=9.6 Hz,1H), 3.38 (s, 3H), 3.79-3.80 (d, J=4.8 Hz, 1H), 4.21-4.25 (m, 2H),6.40-6.42 (d, J=5.2 Hz, 1H), 7.14-7.17 (d, J=8.4 Hz, 1H), 7.19-7.22 (dd,J₁=9.6 Hz, J₂=2.4 Hz, 1H), 7.29-7.31 (d, J=4.8 Hz, 1H), 7.36-7.37 (d,J=6 Hz, 2H), 7.47-7.50 (m, 2H), 7.55-7.59 (q, J=7.6 Hz, 2H), 7.90-7.94(dd, J₁=12.4 Hz, J₂=2.4 Hz, 1H), 8.25-8.28 (d, J=9.2 Hz, 1H), 8.57-8.58(d, J=9.2 Hz, 1H), 10.883 (s, 1H).

Example 15N-(4-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

To a solution ofN-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide(200 mg, 0.389 mmol) in DMA (2 mL) was added3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (193mg, 0.778 mmol) and Cs₂CO₃ (379 mg, 1.167 mmol). The reaction was thenstirred at rt for 40 hrs. The solvent was removed and the residue waspartioned between saturated NaHCO₃ aqueous solution (10 mL) and CHCl₃(30 mL). The organic layer was separated, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo and the residue was purified by asilica gel column chromatography (100:15:1(v/v/v)EtOAc/CH₃OH/Et₃N) toafford the desired compound as a pale yellow solid (171 mg, 66%).

MS (ESI, pos. ion) m/z: 668 (M+1); LC-MS Rt: 3.421 min;

¹H NMR (400 MHz, CDCl₃): δ 0.72-0.77 (m, 2H), 0.82-0.85 (m, 1H),1.08-1.12 (m, 1H), 2.35-2.38 (m, 2H), 2.75 (m, 2H), 2.80 (s, 3H),2.83-2.86 (d, J=6 Hz, 1H), 3.17-3.18 (m, 1H), 3.38 (s, 3H), 3.41-3.46(t, J=10 Hz, 2H), 3.86-3.88 (d, J=4.8 Hz, 1H), 4.02 (s, 3H), 4.30 (m,2H), 6.43-6.44 (d, J=5.2 Hz, 1H), 7.15-7.19 (t, J=8.8 Hz, 1H), 7.29-7.31(d, J=8.8 Hz, 1H), 7.35-7.37 (d, J=7.2 Hz, 2H), 7.46-7.50 (m, 2H),7.55-7.59 (m, 3H), 7.90-7.94 (dd, J₁=8.8 Hz, J₂=8.8 Hz, 1H), 8.45-8.47(d, J=5.2 Hz, 1H), 10.89 (s, 1H).

Example 16N-(5-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)quinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide

To a solution ofN-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide(110 mg, 0.25 mmol) in DMA (2 mL) was added3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (125mg, 0.50 mmol) and Cs₂CO₃ (243 mg, 0.75 mmol). The reaction was thenstirred at rt for 24 hrs. The solvent was removed and the residue waspartioned between saturated NaHCO₃ aqueous solution (10 mL) and CHCl₃(30 mL). The organic layer was separated, dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated in vacuo. The residue waspurified by a silica gel column chromatography(100:15:1(v/v/v)EtOAc/CH₃OH/Et₃N) to afford the desired compound as apale yellow solid (110 mg, 75%).

MS (ESI, pos. ion) m/z: 594 (M+1);

¹H NMR (400 MHz, CDCl₃): δ 0.55 (m, 1H), 0.62 (m, 1H), 0.77 (m, 1H),0.92-0.96 (m, 1H), 1.66-1.69 (q, J₁=7.2 Hz, J₂=8.4 Hz, J₃=4.4 Hz, J₄=5.6Hz, 2H), 1.78-1.81 (q, J₁=7.2 Hz, J₂=8.4 Hz, J₃=4.4 Hz, J₄=5.6 Hz, 2H),2.04-2.09 (m, 2H), 2.36-2.38 (d, J=8.8 Hz, 1H), 2.66-2.72 (m, 2H),2.79-2.83 (dd, J₁=J₂=10 Hz, J₃=J₄=4.8 Hz, 1H), 2.87-2.89 (d, J=8.8 Hz,1H), 2.93-2.95 (d, J=9.6 Hz, 1H), 3.73-3.74 (d, J=4.4 Hz, 1H), 4.19-4.25(m, 2H), 6.38-6.40 (d, J=5.2 Hz, 1H), 7.11-7.15 (t, J₁=8.8 Hz, J₂=7.2Hz, 1H), 7.21-7.24 (dd, J₁=J₂=9.2 Hz, J₃=J₄=2.8 Hz, 1H), 7.31-7.35 (t,J₁=J₂=7.2 Hz, 2H), 7.50-7.51 (d, J=2.8 Hz, 1H), 7.55-7.58 (m, 3H),8.18-8.21 (d, J=9.2 Hz, 1H), 8.23-8.23 (d, J=2.4 Hz, 1H), 8.27-8.29 (d,J=9.2 Hz, 1H), 8.58-8.59 (d, J=5.2 Hz, 1H).

Example 17N-(4-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide

To a solution ofN-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1-dicarboxamide(260 mg, 0.534 mmol) in DMA (3 mL) was added3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (266mg, 1.068 mmol) and Cs₂CO₃ (520 mg, 1.602 mmol). The reaction was thenstirred at rt for 2 days. The solvent was removed and the residue waspartioned between saturated NaHCO₃ aqueous solution (15 mL) and CHCl₃(30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andthe filtrate was concentrated in vacuo. The residue was purified by asilica gel column chromatography (100:15:1(v/v/v)EtOAc/CH₃OH/Et₃N) toafford the desired compound as a pale yellow solid (264 mg, 77%).

MS (ESI, pos. ion) m/z: 641(M+1); LC-MS Rt: 3.439 min;

¹H NMR (400 MHz, CDCl₃): δ 0.61 (m, 2H), 0.75 (m, 1H), 0.96 (m, 1H),1.59-1.62 (q, J₁=7.2 Hz, J₂=8 Hz, J₃=4.4 Hz, J₄=5.2 Hz, 2H), 1.81-1.84(q, J₁=7.6 Hz, J₂=8.4 Hz, J₃=4.4 Hz, J₄=5.2 Hz, 2H), 2.07-2.15 (m, 2H),2.36-2.38 (d, J=8.8 Hz, 1H), 2.64-2.73 (m, 2H), 2.76-2.80 (dd, J₁=9.6Hz, J₂=9.2 Hz, J₃=4.4 Hz, J₄=4.8 Hz, 1H), 2.92-2.94 (d, J=8.8 Hz, 1H),2.99-3.02 (d, J=10 Hz, 1H), 3.73-3.74 (d, J=3.6 Hz, 1H), 4.041 (s, 3H),4.30-4.32 (m, 2H), 6.38-6.39 (d, J=5.2 Hz, 1H), 7.19-7.23 (t, J₁=8.8 Hz,J₂=8 Hz, 1H), 7.30-7.30 (d, J=6.4 Hz, 1H), 7.36-7.40 (t, J₁=8.4 Hz,J₂=7.6 Hz, 2H), 7.48-7.50 (d, J=9.6 Hz, 2H), 7.56 (s, 1H), 7.70 (s, 1H),7.76-7.80 (dd, J₁=J₂=12 Hz, J₃=J₄=2.4 Hz, 1H), 8.15 (s, 1H), 8.45-8.46(d, J=5.2 Hz, 1H), 10.24 (s, 1H).

Example 18N-(4-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution ofN-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(240 mg, 0.475 mmol) in DMA (3 mL) was added3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (236mg, 0.95 mmol) and Cs₂CO₃ (463 mg, 1.425 mmol). The reaction was thenstirred at rt for 2 days. The solvent was removed and the residue waspartioned between saturated NaHCO₃ aqueous solution (15 mL) and CHCl₃(30 mL). The organic layer was separated, dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated in vacuo. The residue waspurified by a silica gel column chromatography(100:15:1(v/v/v)EtOAc/CH₃OH/Et₃N) to afford the desired compound as awhite solid (250 mg, 80%).

MS (ESI, pos. ion) m/z: 659 (M+1);

¹H NMR (400 MHz, CDCl₃): δ 0.58-0.66 (m, 2H), 0.74-0.78 (m, 1H),0.95-1.00 (m, 1H), 1.62-1.65 (q, J₁=7.6 Hz, J₂=8.4 Hz, J₃=4.4 Hz, J₄=5.2Hz, 2H), 1.79-1.82 (q, J₁=7.2 Hz, J₂=8.4 Hz, J₃=4.4 Hz, J₄=5.6 Hz, 2H),2.05-2.16 (m, 2H), 2.39-2.42 (d, J=8.8 Hz, 1H), 2.68-2.77 (m, 2H),2.80-2.83 (dd, J₁=J₂=10 Hz, J₃=J₄=4.8 Hz, 1H), 2.96-2.98 (d, J=8.8 Hz,1H), 3.03-3.05 (d, J=10 Hz, 1H), 3.74-3.75 (d, J=3.6 Hz, 1H), 4.04 (s,3H), 4.30-4.31 (m, 2H), 6.38-6.39 (d, J=5.6 Hz, 1H), 7.05-7.08 (d, J=6.4Hz, 2H), 7.19-7.23 (t, J₁=J₂=8.4 Hz, 1H), 7.27-7.29 (d, J=9.6 Hz, 1H),7.41-7.47 (q, J₁=J₂=6.8 Hz, J₃=J₄=4.8 Hz, 1H), 7.56 (s, 1H), 7.69 (s,1H), 7.75-7.78 (dd, J₁=J₂=12 Hz, J₃=J₄=2.4 Hz, 1H), 8.38 (s, 1H),8.44-8.46 (d, J=5.6 Hz, 1H).

Example 19N-(5-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)-6-methoxyquinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide

To a solution ofN-(5-(7-hydroxy-6-methoxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide(200 mg, 0.402 mmol) in DMA (4 mL) was added3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (150mg, 0.603 mmol) and Cs₂CO₃ (261 mg, 0.804 mmol). The reaction was thenstirred at rt for 24 hrs. The solvent was removed and the residue waspartioned between saturated NaHCO₃ aqueous solution (5 mL) and CHCl₃ (25mL). The organic layer was separated, dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated in vacuo. The residue waspurified by a silica gel column chromatography (100:15:1(v/v/v)EtOAc/CH₃OH/Et₃N) to afford the desired compound as a pale yellowsolid (165 mg, 63%).

MS (ESI, pos. ion) m/z: 651(M+1); LC-MS Rt: 3.296 min;

¹H NMR (400 MHz, CDCl₃): δ 0.78 (m, 1H), 0.79 (m, 1H), 0.86 (m, 1H),0.90 (m, 1H), 1.10 (s, 3H), 1.37 (m, 2H), 1.40 (s, 2H), 1.43 (s, 2H),2.80 (d, 3H), 3.14 (m, 2H), 3.38 (s, 3H), 4.02 (s, 3H), 4.29 (s, 1H),6.46 (d, J=5.2 Hz, 1H), 7.36-7.39 (d, 2H), 7.46-7.57 (m, 6H), 8.24 (d,J=2.8 Hz, 1H), 8.38 (d, J=9.2 Hz, 1H), 8.49 (d, J=5.2 Hz, 1H), 11.28 (s,1H).

Example 20N-(5-(7-(3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propoxy)-6-methoxyquinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide

To a solution ofN-(5-(7-hydroxy-6-methoxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide(300 mg, 0.640 mmol) in DMA (4 mL) was added3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (239mg, 0.960 mmol) and Cs₂CO₃ (416 mg, 1.280 mmol). The reaction was thenstirred at rt for 48 hrs. The solvent was removed and the residue waspartioned between saturated NaHCO₃ aqueous solution (5 mL) and CHCl₃ (25mL). The organic layer was separated, dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated in vacuo. The residue waspurified by a silica gel column chromatography (100:15:1(v/v/v)EtOAc/CH₃OH/Et₃N) to afford the desired compound as a pale yellowsolid (240 mg, 60%).

MS (ESI, pos. ion) m/z: 624 (M+1);

¹H NMR (400 MHz, CDCl₃): δ 0.71 (m, 2H), 0.85 (m, 2H), 1.25 (m, 2H),1.42 (m, 2H), 1.69 (m, 2H), 1.79 (m, 2H), 2.23 (m, 2H), 3.12 (dd, 1H),3.25 (m, 2H), 3.82 (d, 1H), 4.03 (s, 3H), 4.32 (m, 2H), 6.42 (d, J=5.2Hz, 1H), 7.15 (t, J₁=8.8 Hz, J₂=7.2 Hz, 1H), 7.30 (dd, J₁=J₂=9.2 Hz,J₃=J₄=2.8 Hz, 1H), 7.37 (t, J₁=J₂=7.2 Hz, 2H), 7.52 (d, J=2.8 Hz, 1H),7.56 (m, 4H), 8.30 (d, J=9.2 Hz, 1H), 8.49-8.23 (d, J=2.4 Hz, 1H), 9.41(s, 1H).

Example 21N-(4-(7-(4-oxaspiro[2.4]heptane-6-yloxy)quinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide

Step 1) diethyl cyclopropane-1,1-dicarboxylate

To a solution of diethyl malonate (3.2 g, 20 mmol) and anhydrouspotassium carbonate powder (6.9 g, 50 mmol) in DMF (50.0 mL) was added1,2-dibromoethane (4.136 g, 22 mmol). After stirring for 2 hrs,catalytic amount of TBAI (0.738 g, 2.0 mmol) was added and the mixturewas continued to stir at room temperature for 8 hrs. The reactionmixture was filtered and the solid was washed with diethyl ether 3times. The filtrate was diluted with water (200 mL) and extracted withdiethyl ether (75 mL×4). The combined organic phases were washed with 70mL of brine, dried over Na₂SO₄ and concentrated in vacuo. The residuewas chromatographed with a short alumina column (1:10 (v/v)EtOAc/n-hexane) to afford the desired compound as yellow oil (3.3 g,88.7%).

¹H NMR (400 MHz, CDCl₃): δ 1.27 (m, J=6.8 Hz, 6H), 1.42 (m, 4H), 4.18(m, 4H).

Step 2) 1-(ethoxycarbonyl)cyclopropanecarboxylic acid

To a solution of diethyl cyclopropane-1,1-dicarboxylate (4.77 g, 25.6mmol) in ethanol (40 mL) was added KOH (1.43 g, 25.6 mmol) in H₂O (8mL), and the reaction mixture was stirred at room temperature overnight.The ethanol was removed under reduced pressure. The residue wasneutralized with HCl (6 mL, 5 mol/L), then extracted with EtOAc (100mL×3). The combined organic phases were dried over Na₂SO₄, filtered andthe filtrate was concentrated in vacuo to give the title compound as awhite solid (3.58 g, 88.4%).

¹H NMR (400 MHz, CDCl₃): δ 1.27 (t, J=6.7 Hz, 3H), 1.83 (m, 2H), 1.86(m, 2H), 4.25 (m, 2H).

Step 3) ethyl 1-(phenyl carbamoyl)cyclopropane carboxylate

To a solution of 1-(ethoxycarbonyl)cyclopropane carboxylic acid (7.4 g,46.84 mmol) in dry CH₂Cl₂ (70 mL) was added HATU (35.62 g, 93.67 mmol)at 0° C. After stirring for 10 minutes, a solution of the aniline (8.71g, 93.67 mmol) and Et₃N-(9.48 g, 93.67 mmol) in dry CH₂Cl₂ (30 mL) wasthen added and the reaction mixture was continued to stir at 40° C. for24 hrs. The reaction mixture was quenched with water (30 mL) andextracted with CH₂Cl₂ (100 mL×3). The combined organic phases were driedover anhydrous Na₂SO₄, filtered and the filtrate was concentrated invacuo. The residue was chromatographed with a silica gel column (1:5(v/v) EtOAc/n-hexane) to afford the title compound as a pale yellowsolid (9.7 g, 89%).

¹H NMR (400 MHz, CDCl₃): δ 1.27 (t, J=6.8 Hz, 3H), 1.76 (m, 2H), 1.85(m, 2H), 4.20 (m, 2H), 6.68-6.71 (m, 1H), 7.32-7.35 (m, 2H), 7.57-7.60(m, 2H), 10.88 (s, 1H).

Step 4) 1-(phenylcarbamoyl)cyclopropanecarboxylic acid

To a solution of ethyl 1-(phenyl carbamoyl)cyclopropane carboxylate (13g, 55.79 mmol) in ethanol/THF (1/1, 100 mL) was added KOH (4.69 g, 83.69mmol) in H₂O (8 mL) and the mixture was stirred at room temperatureovernight. The ethanol and THF were removed under reduced pressure. Theresidue was neutralized with HCl (5 mol/L, 20 mL), and extracted withEtOAc (150 mL×3). The combined organic phases were dried over Na₂SO₄,filtered and the filtrate was concentrated in vacuo to afford the titlecompound as a white solid (10.1 g, 88.6%).

¹H NMR (400 MHz, CDCl₃): δ 1.77 (m, 2H), 1.84 (m, 2H), 7.10 (m, 1H),7.30-7.34 (m, 2H), 7.53-7.55 (m, 2H), 10.61 (s, 1H).

Step 5)N-(4-(7-(benzyloxy)quinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide

To a solution of 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (1.14 g,5.6 mmol) in dry CH₂Cl₂ (8 mL) was added HATU (2.11 g, 5.6 mmol) at 0°C. After stirring for 10 minutes, a solution of the4-(7-(benzyloxy)quinolin-4-yloxy)-3-fluorobenzenamine (1.0 g, 2.8 mmol)and Et₃N-(0.7 g, 6.9 mmol) in dry CH₂Cl₂ (5 mL) was added. The reactionmixture was stirred at 40° C. for 24 hrs, quenched with water (10 mL),and extracted with CH₂Cl₂ (30 mL×3). The combined organic phases weredried over anhydrous Na₂SO₄, filtered and the filtrate was concentratedin vacuo. The residue was chromatographed with a silica gel column (1:1(v/v) EtOAc/n-hexane) to afford the title compound as a white solid (1.3g, 85%).

MS (ESI, pos. ion) m/z: 548 (M+1); LC-MS Rt: 4.595 min;

¹H NMR (400 MHz, CDCl₃): δ 1.60 (m, 2H), 1.83 (m, 2H), 5.25 (s, 2H),6.45 (m, 1H), 7.28-7.29 (m, 1H), 7.16-7.24 (m, 2H), 7.34-7.57 (m, 10H),7.78-7.81 (m, 1H), 7.99 (s, 1H), 8.30 (d, J=9.2 Hz, 1H), 8.60 (d, J=6Hz, 1H), 10.29 (s, 1H).

Step 6)N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide

A solution ofN-(4-(7-(benzyloxy)quinolin-4-yloxy)-3-fluorophenyl)-N-phenyl-cyclopropane-1,1-dicarboxamide(0.7 g, 1.28 mmol) and Pd/C (0.8 g) in methanol (20 mL) under H₂ wasstirred at room temperature for 1.5 hrs, then the reaction mixture wasfiltered and washed with methanol (3×10 mL). The combined organicsolvent was concentrated in vacuo to giveN-(5-(7-hydroxy-quinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamideas a white solid (0.53 g, 90.6%).

MS (ESI, pos. ion) m/z: 457 (M+1); LC-MS Rt: 3.936 min;

¹H NMR (400 MHz, MeOD): δ 1.66 (s, 1H), 6.81 (d, J=6.4 Hz, 1H), 7.14 (t,J=7.6 Hz, 1H), 7.33 (m, 3H), 7.41-7.48 (m, 3H), 7.55 (d, J=8 Hz, 2H),7.92 (d, J=12.8 Hz, 1H), 8.49 (d, J=8.8 Hz, 1H), 8.69 (d, J=6 Hz, 1H).

Step 7)N-(4-(7-(4-oxaspiro[2.4]heptane-6-yloxy)quinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide

To a mixture of (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (168 mg,0.877 mmol, from example 6) andN-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide(300 mg, 0.584 mmol) in 5 mL of N,N-dimethylacetamide was added cesiumcarbonate (893 mg, 2.74 mmol). After stirring at room temperature for 36hrs, the reaction mixture was warmed up to 40° C. and continued to stirfor 8 hrs. The reaction mixture was concentrated in vacuo and theresidue was chromatographed with a silica gel column (1:1 (v/v)EtOAc/n-hexane) to afford the title compound as a white solid (65 mg,18%).

MS (ESI, pos. ion) m/z: 554.1 (M+1); LC-MS Rt: 4.354 min;

¹H NMR (400 MHz, CDCl₃): δ 0.53 (m, 1H), 0.65 (m, 1H), 0.89 (m, 1H),1.00 (m, 1H), 1.60 (m, 2H), 1.84 (m, 2H), 2.25 (m, 1H), 2.53 (m, 1H),4.20 (m, 2H), 5.22 (m, 1H), 6.39 (d, J=5.2 Hz, 1H), 7.19 (m, 2H), 7.28(m, 2H), 7.38 (m, 2H), 7.48 (m, 2H), 7.77 (m, 1H), 7.59 (s, 1H), 8.28(d, J=9.2 Hz, 1H), 8.58 (d, J=5.2 Hz, 1H).

Example 22N-(4-(7-(((5R)-4-oxaspiro[2.4]heptane-5-yl)methoxy)quinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide

To a mixture of ((5S)-4-oxaspiro[2.4]heptane-5-yl)methylmethanesulfonate (181.2 mg, 0.877 mmol, from example 2) andN-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenyl-cyclopropane-1,1-dicarboxamide(300 mg, 0.656 mmol) in 5 mL of N,N-dimethylacetamide was added cesiumcarbonate (893 mg, 2.74 mmol). After stirring at room temperature for 36hrs, then the reaction mixture was warmed up to 40° C. and stirred for 8hrs. The reaction mixture was concentrated in vacuo and the residue waschromatographed with a silica gel column (1:1 (v/v) EtOAc/n-hexane) togive the title compound as a white solid (234 mg, 63%).

MS (ESI, pos. ion) m/z: 568.2 (M+1); LC-MS Rt: 4.364 min;

¹H NMR (400 MHz, CDCl₃): δ0.56 (m, 2H), 0.91 (m, 2H), 1.60 (m, 4H), 1.83(m, 2H), 2.03 (m, 2H), 4.18 (m, 2H), 4.52 (s, 1H), 6.38 (m, 1H), 7.20(m, 2H), 7.30 (m, 1H), 7.38 (m, 3H), 7.48 (m, 2H), 7.76 (m, 1H), 8.02(s, 1H), 8.25 (d, J=9.2 Hz, 1H), 8.58 (d, J=5.2 Hz, 1H), 10.18 (s, 1H).

Example 23N-(4-(7-(3-(1-hydroxycyclopropyl)propoxy)quinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide

To a mixture of 3-(1-hydroxycyclopropyl)propyl methanesulfonate (170.7mg, 0.877 mmol, from example 9) andN-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide(300 mg, 0.656 mmol) in 5 mL of N,N-dimethylacetamide was added cesiumcarbonate (893 mg, 2.74 mmol). After stirring at room temperature for 36hrs, then the reaction mixture was warmed to 40° C. for 8 hrs. Thereaction mixture was concentrated in vacuo and the residue waschromatographed with a silica gel column (4:1 (v/v) EtOAc/n-hexane) toafford the title compound as a white solid (364.1 mg, 74%).

MS (ESI, pos. ion) m/z: 556.2 (M+1); LC-MS Rt: 4.110 min;

¹H NMR (400 MHz, CDCl₃): δ 0.51 (s, 2H), 0.79 (s, 2H), 1.25 (s, 2H),1.81 (m, 4H), 2.15 (m, 2H), 3.38 (s, 3H), 4.24 (m, 2H), 6.38 (d, J=4.8Hz, 1H), 7.25 (m, 4H), 7.46 (m, 1H), 7.77 (d, J=12 Hz, 1H), 7.97 (s,1H), 8.26 (d, J=9.2 Hz, 1H), 8.58 (d, J=4.8 Hz, 1H), 10.18 (s, 1H).

Example 24N-(5-(7-(4-oxaspiro[2.4]heptane-6-yloxy)quinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide

Step 1)N-(5-(7-(benzyloxy)quinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide

The title compound was prepared according to the procedure described inExample 21 of step 5 by using 1-(phenylcarbamoyl)cyclopropanecarboxylicacid (1.14 g, 5.6 mmol), HATU (2.11 g, 5.6 mmol),5-(7-(benzyloxy)quinolin-4-yloxy)pyridin-2-amine (960 mg, 2.8 mmol) andDBU (868 mg, 7.0 mmol) in dry DCM (50 mL). The title compound wasobtained as a white solid (1.22 g, 82%).

MS (ESI, pos. ion) m/z: 531.1 (M+1); LC-MS Rt: 4.583 min;

¹H NMR (400 MHz, CDCl₃): δ 1.67 (m, 2H), 1.80 (m, 2H), 5.24 (s, 2H),6.43 (d, J=4.8 Hz, 1H), 7.14 (m, 1H), 7.34 (m, 4H), 7.41 (m, 2H), 7.43(m, 3H), 7.51 (m, 3H), 8.24 (m, 2H), 8.30 (d, J=8.8 Hz, 1H), 8.61 (d,J=5.2 Hz, 1H), 9.10 (s, 1H), 9.44 (s, 1H).

Step 2)N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide

A solution ofN-(5-(7-(benzyloxy)quinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide(1.22 g, 2.3 mmol) and Pd/C (1.2 g) in methanol (30 mL) under H₂ wasstirred at room temperature for 2 hrs, then the reaction mixture wasfiltered and washed with methanol (10 mL×3). The combined solvent wasconcentrated in vacuo to giveN-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenyl-cyclopropane-1,1-dicarboxamideas a white solid (910.8 mg, 90%).

MS (ESI, pos. ion) m/z: 441.2 (M+1); LC-MS Rt: 3.508 min;

¹H NMR (400 MHz, CD₃OD): δ 1.69 (m, 4H), 6.55 (d, J=5.6 Hz, 1H), 7.14(m, 1H), 7.30 (m, 4H), 7.56 (m, 2H), 7.74 (m, 1H), 8.29 (m, 3H), 8.55(d, J=5.6 Hz, 1H).

Step 3)N-(5-(7-(4-oxaspiro[2.4]heptane-6-yloxy)quinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide

To a mixture of (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (168 mg,0.877 mmol) andN-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide(300 mg, 0.682 mmol) in 5 mL of N,N-dimethylacetamide was added cesiumcarbonate (893 mg, 2.74 mmol). After stirring at room temperature for 36hrs, then the reaction mixture was warmed up to 40° C. for 8 hrs. Thereaction mixture was concentrated in vacuo and the residue waschromatographed with a silica gel column (2:1 (v/v) EtOAc/n-hexane) toafford the title compound as a white solid (73 mg, 20%).

MS (ESI, pos. ion) m/z: 537.1 (M+1); LC-MS Rt: 4.429 min;

¹H NMR (400 MHz, CDCl₃): δ 0.60 (m, 2H), 0.95 (m, 2H), 1.70 (m, 4H),2.40 (m, 1H), 2.54 (m, 1H), 4.19 (m, 2H), 5.23 (m, 1H), 6.42 (d, J=4.2Hz, 1H), 7.28 (m, 3H), 7.34 (m, 3H), 7.58 (m, 3H), 8.24 (m, 2H), 8.62(d, J=5.2 Hz, 1H), 9.10 (s, 1H).

Example 25N-(5-(7-(3-(1-hydroxycyclopropyl)propoxy)quinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide

The title compound was prepared according to the procedure described inExample 9 by usingN-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenyl-cyclopropane-1,1-dicarboxamide(300 mg, 0.682 mmol), 3-(1-hydroxycyclopropyl)-propyl methanesulfonate(155 mg, 0.80 mmol), and Cs₂CO₃ (668 mg, 2.05 mmol) in 3 mL of DMA. Theresidue was purified by a silical gel column chromatography (3:1 (v/v)EtOAc/n-hexane) to give the title compound as a white solid (238.5 mg,65%).

MS (ESI, pos. ion) m/z: 539.2 (M+1); LC-MS Rt: 4.156 min;

¹H NMR (400 MHz, CDCl₃): δ0.51 (m, 2H), 0.81 (m, 2H), 1.69 (m, 2H), 1.82(m, 4H), 2.15 (m, 2H), 4.25 (m, 2H), 6.42 (d, J=5.2 Hz, 1H), 7.16 (m,1H), 7.23 (d, J=2.8 Hz, 1H), 7.36 (m, 2H), 7.44 (d, J=2.4 Hz, 1H), 7.58(m, 3H), 8.24 (m, 2H), 8.31 (d, J=8.8 Hz, 1H), 8.62 (d, J=5.2 Hz, 1H).

Chromatography separation also provided N-(5-(7-(3-(1-cyclopropylmethanesulfonate-1-yl)propoxy)quinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamideas a pale yellow solid.

MS (ESI, pos. ion) m/z: 617.1 (M+1); LC-MS Rt: 4.491 min;

¹H NMR (400 MHz, CDCl₃): δ0.78 (m, 2H), 1.31 (m, 2H), 1.67 (m, 2H), 1.81(m, 2H), 2.14 (m, 4H), 3.02 (s, 3H), 4.23 (m, 2H), 6.41 (d, J=5.2 Hz,1H), 7.14 (m, 1H), 7.22 (m, 2H), 7.35 (m, 2H), 7.41 (d, J=2.4 Hz, 1H),7.58 (m, 3H), 8.22 (m, 2H), 8.30 (d, J=9.2 Hz, 1H), 8.61 (d, J=5.2 Hz,1H), 9.09 (s, 1H), 9.43 (s, 1H).

Example 26N-(4-(7-(4-oxaspiro[2.4]heptane-6-yloxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide

The title compound was prepared according to the procedure described inExample 24 by using (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (138mg, 0.72 mmol),N-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide(300 mg, 0.616 mmol), and Cs₂CO₃ (602.5 mg, 1.848 mmol) in 3 mL of DMA.The residue was purified by a silical gel column chromatography (2:1(v/v) EtOAc/n-hexane). The title compound was obtained as a white solid(186.7 mg, 52%).

MS (ESI, pos. ion) m/z: 583.9 (M+1); LC-MS Rt: 4.432 min;

¹H NMR (400 MHz, CDCl₃): δ0.55 (m, 1H), 0.65 (m, 1H), 0.90 (m, 1H), 1.05(m, 1H), 1.60 (m, 2H), 1.85 (m, 2H), 4.04 (s, 3H), 4.24 (m, 2H), 5.25(m, 1H), 6.41 (d, J=4.4 Hz, 1H), 7.20 (m, 2H), 7.25 (m, 1H), 7.30 (m,2H), 7.40 (m, 1H), 7.50 (m, 2H), 7.60 (s, 1H), 7.80 (m, 2H), 7.95 (m,1H) 8.50 (d, J=5.2 Hz, 1H), 10.25 (s, 1H).

Example 27 N-(4 (7 (3 (1hydroxycyclopropyl)propoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide

The title compound was prepared according to the procedure described inExample 9 by usingN-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide(300 mg, 0.616 mmol), 3-(1-hydroxycyclopropyl)propyl methanesulfonate(155 mg, 0.80 mmol), and Cs₂CO₃ (602.5 mg, 1.848 mmol) in 3 mL of DMA.The residue was purified by a silical gel column chromatography (6:1(v/v) EtOAc/n-hexane). The title compound was obtained as a white solid(263 mg, 73%).

MS (ESI, pos. ion) m/z: 586.2 (M+1); LC-MS Rt: 4.244 min;

¹H NMR (400 MHz, CDCl₃): δ0.46 (s, 2H), 0.76 (m, 2H), 1.61 (m, 2H), 1.84(m, 4H), 2.22 (t, J=6.4 Hz, 2H), 4.03 (s, 3H), 4.30 (t, J=6 Hz, 2H),6.41 (m, 1H), 7.21-7.58 (m, 8H), 7.80 (m, 1H), 7.95 (s, 1H), 8.49 (d,J=5.2 Hz, 1H), 10.24 (s, 1H).

N-(4-(7-(3-(1-cyclopropylmethanesulfonate-1-yl)propoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamidewas obtained as a pale yellow solid.

MS (ESI, pos. ion) m/z: 664.2 (M+1); LC-MS Rt: 4.563 min;

¹H NMR (400 MHz, CDCl₃): δ0.78 (m, 2H), 1.30 (m, 2H), 1.60 (m, 2H), 1.85(m, 2H), 2.11 (m, 2H), 2.25 (m, 2H), 3.06 (s, 3H), 4.03 (s, 3H), 4.28(m, 2H), 6.41 (d, J=4.8 Hz, 1H), 7.22 (m, 2H), 7.27 (m, 3H), 7.39 (m,2H), 7.49 (d, J=8 Hz, 1H), 7.57 (s, 1H), 7.79 (d, J=12 Hz, 1H), 7.94 (s,1H).

Example 28 N-(4-(7-(3-(1hydroxycyclopropyl)propoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

The title compound was prepared according to the procedure described inExample 9 by usingN-(4-(7-hydroxy-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(300 mg, 0.594 mmol), 3-(1-hydroxycyclopropyl)propyl methanesulfonate(155 mg, 0.80 mmol), and Cs₂CO₃ (581 mg, 1.782 mmol) in 3 mL of DMA. Theresidue was purified by a silical gel column chromatography (6:1 (v/v)EtOAc/n-hexane). The title compound was obtained as a white solid (247mg, 69%).

MS (ESI, pos. ion) m/z: 604.2 (M+1); Rt: 4.240 min;

¹H NMR (400 MHz, CDCl₃): δ0.46 (m, 2H), 0.75 (m, 2H), 1.64 (m, 2H), 1.83(m, 4H), 2.22 (m, 2H), 4.03 (s, 3H), 4.31 (m, 2H), 6.41 (m, 1H), 7.08(m, 2H), 7.25 (m, 1H), 7.46-7.79 (m, 5H), 8.19 (s, 1H), 8.49 (d, J=5.2Hz, 1H), 10.00 (s, 1H).

Biological Testing

The efficacy of the compounds of the invention as inhibitors of receptortyrosine kinases, such as c-Met, KDR and/or IGF 1R related activity andas anti-tumor agents in xenograft animal models can be evaluated asfollows.

MTT Cell Assay

Preparation Instructions: MTT((3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) issoluble in water (10 mg/ml), ethanol (20 mg/ml) and is also soluble inbuffered salt solutions and culture media (5 mg/ml).

-   MTT Solution: 5 mg/ml MTT in PBS. Solution must be filter sterilized    after adding MTT.-   MTT Solvent: 4 mM HCl, 0.1% Nondet P-40 (NP40) all in isopropanol.    Procedure:-   Short 96 well assay: EACH condition was done in triplicate or more.-   1. DAY ONE: Trypsinized one T-25 flask and added 5 ml of complete    media to trypsinized cells. Centrifuged in a sterile 15 ml falcon    tube at 500 rpm in the swinging bucked rotor (˜400×g) for 5 min.-   2. Removed media and resuspended cells to 1.0 ml with complete    media.-   3. Counted and recorded cells per ml.-   4. Diluted the cells (cv=cv) to 75,000 cells per ml. Used completed    media to dilute cells.-   5. Added 100 μl of cells (7500 total cells) into each well and    incubated overnight.-   6. DAY TWO: Treated cells on day two with inhibitors.    -   Final volume was 100 μl per well.-   7. DAY THREE: Added 20 μl of 5 mg/ml MTT to each well. Included one    set of wells with MTT but no cells (control).-   8. Incubated for 3.5 hours at 37° C. in culture hood.-   9. Carefully removed media.-   10. Added 150 μl MTT solvent.-   11. Covered with tinfoil and agitate cells on orbital shaker for 15    min.-   12. Read absorbance at 590 nm with a reference filter of 620 nm.    Kinase Assays

Kinase assays can be performed by measurement of incorporation of γ-³³PATP into immobilized myelin basic protein (MBP). High binding white 384well plates (Greiner) are coated with MBP (Sigma #M-1891) by incubationof 60 μl/well of 20 μg/ml MBP in Tris-buffered saline (TBS; 50 mM TrispH 8.0, 138 mM NaCl, 2.7 mM KCl) for 24 hours at 4° C. Plates are washed3× with 100 μl TBS. Kinase reactions are carried out in a total volumeof 34 μl in kinase buffer (5 mM Hepes pH 7.6, 15 mM NaCl, 0.01% bovinegamma globulin (Sigma #I-5506), 10 mM MgCl₂, 1 mM DTT, 0.02%TritonX-100). Compound dilutions are performed in DMSO and added toassay wells to a final DMSO concentration of 1%. Each data point ismeasured in duplicate, and at least two duplicate assays are performedfor each individual compound determination. Enzyme is added to finalconcentrations of 10 nM or 20 nM, for example. A mixture of unlabeledATP and γ-³³P ATP is added to start the reaction (2×10⁶ cpm of γ-³³P ATPper well (3000 Ci/mmole) and either 10 μM unlabeled ATP, typically. Thereactions are carried out for 1 hour at room temperature with shaking.Plates are washed 7× with TBS, followed by the addition of 50 μl/wellscintillation fluid (Wallac). Plates are read using a Wallac Triluxcounter. This is only one format of such assays, various other formatsare possible, as known to one skilled in the art.

The above assay procedure can be used to determine the IC₅₀ forinhibition and/or the inhibition constant, K_(i). The IC₅₀ is defined asthe concentration of compound required to reduce the enzyme activity by50% under the condition of the assay. Exemplary compositions have IC₅₀'sof, for example, less than about 100 μM, less than about 10 μM, lessthan about 1 μM, and further for example having IC₅₀'s of less thanabout 100 nM, and still further, for example, less than about 10 nM. TheK_(i) for a compound may be determined from the IC₅₀ based on threeassumptions. First, only one compound molecule binds to the enzyme andthere is no cooperativity. Second, the concentration of active enzymeand the compound tested are known (i.e., there are no significantamounts of impurities or inactive forms in the preparations). Third, theenzymatic rate of the enzyme-inhibitor complex is zero.

Kinase inhibition and cellular assays.

In vitro kinase assays can also be done to establish IC₅₀ values againsta variety of recombinant receptor and nonreceptor kinases. Optimalenzyme, ATP, and substrate (gastrin peptide) concentrations areestablished for each enzyme using homogeneous time-resolved fluorescence(HTRF) assays. Compouns are tested in a 10-point dose-response curve foreach enzyme using an ATP concentration of two-thirds Km for each. Mostassays consist of enzyme mixed with kinase reaction buffer [20 mmol/LTris-HCl (pH 7.5), 10 mmol/L MgCl₂, 5 mmol/L MnCl₂, 100 mmol/L NaCl, 1.5mmol/L EGTA]. A final concentration of 1 mmol/L DTT, 0.2 mmol/L NaVO₄,and 20 Ag/mL BSA is added before each assay. For Src, a modified kinasereaction buffer is used that included 20 mmol/L Tris-HCl (pH 7.5), 2.5mmol/L MnCl₂, 100 mmol/L NaCl, and 1.5 mmol/L EGTA. A finalconcentration of 1 mmol/L DTT, 0.2 mmol/L NaVO₄, and 20 Ag/mL BSA isadded before each assay. For all assays, 5.75 mg/mLstreptavidin-allophycocyanin (ProZyme, San Leandro, Calif.) and 0.1125nmol/L Eu-PT66 (Perkin-Elmer Corp., Boston, Mass.) are added immediatelybefore the HTRF reaction. Plates are incubated for 30 minutes at roomtemperature and read on a Discovery instrument (Packard Instrument Co.,Downers Grove, Ill.).

c-Met Assay

c-Met biochemical activity can be assessed using a Luciferase-CoupledChemilumineacent Kinase assay (LCCA) format as described above. Again,kinase activity is measured as the percent ATP remaining following thekinase reaction. Remaining ATP is detected byluciferase-luciferin-couple chemiluminescence. Specifically, thereaction is initiated by mixing test compounds, 1 μM ATP, 1 μM poly-EYand 10 nM c-Met (baculovirus expressed human c-Met kinase domainP948-S1343) in a 20 μL assay buffer (20 mM Tris-HCL pH7.5, 10 mM MgCl₂,0.02% Triton X-100, 100 mM DTT, 2 mM MnCl₂). The mixture is incubated atambient temperature for 2 hours after which 20 μL luciferase-luciferinmix is added and the chemiluminescent signal read using a Wallac Victor²reader. The luciferase-luciferin mix consists of 50 mM HEPES, pH 7.8,8.5 μg/mL oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100,0.25 mg/mL coenzyme A, 63 μM AMP, 28 μg/mL luciferin and 40000 units oflight/mL luciferase.

Tumor Xenograft Models

Human glioma tumor cells (U87MG cells, ATCC) are expanded in culture,harvested and injected subcutaneously into 5-8 week old female nude mice(CD1 nu/nu, Charles River Labs) (n=10). Subsequent administration ofcompound by oral gavage or by IP (10-100 mpk/dose) begins anywhere fromday 0 to day 29 post tumor cell challenge and generally continues eitheronce or twice a day for the duration of the experiment. Progression oftumor growth is followed by three dimensional caliper measurements andrecorded as a function of time. Intial statistical analysis is done byrepeated measures analysis of variance (RMANOVA), followed by Scheffepost hoc testing for multiple comparisons. Vehicle alone (captisol, orthe like) is the negative control.

Human gastric adenocarcinoma tumor cells (MKN45 cells, ATCC) areexpanded in culture, harvested and injected subcutaneously into 5-8 weekold female nude mice (CD1 nu/nu, Charles River Labs) (n=10). Subsequentadministration of compound by oral gavage or by IP (10-100 mpk/dose)begins anywhere from day 0 to day 29 post tumor cell challenge andgenerally continues either once or twice a day for the duration of theexperiment. Progression of tumor growth is followed by three dimensionalcaliper measurements and recorded as a function of time. Initialstatistical analysis is done by repeated measures analysis of variance(RMANOVA), followed by Scheffe post hoc testing for multiplecomparisons. Vehicle alone (captisol, or the like) is the negativecontrol.

A431 cells were cultured in DMEM (low glucose) with 10% FBS andpenicillin/streptomycin/glutamine. Cells are harvested bytrypsinization, washed, and adjusted to a concentration of 5×10⁷/mL inserum-free medium Animals are challenged s.c. with 1×10⁷ cells in 0.2 mLover the left flank. Approximately 10 days thereafter, mice arerandomized based on initial tumor volume measurements and treated witheither vehicle (Ora-Plus) or test compounds. Tumor volumes and bodyweights are recorded twice weekly and/or on the day of sacrifice. Tumorvolume is measured with a Pro-Max electronic digital caliper (Sylvac,Crissier, Switzerland) and calculated using the Formula length (mm)×width (mm)× height (mm) and expressed in mm³ Data are expressed asmean±SE. Repeated measures ANOVA followed by Scheffe post hoc testingfor multiple comparisons was used to evaluate the statisticalsignificance of observed differences.

1. A compound of Formula (I):

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide or apharmaceutically acceptable salt thereof, wherein: Q₁ is formula (IIb):

Q₂ is formula (III):

R¹ is —OC(═O)NR⁵R^(5a), —OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a),—NR⁵C(═O)—R^(5a), R⁵R^(5a)N—O₂S—, R⁵O₂S—, R⁵O₂SR^(5a)N—, R⁵S(═O)-alkyl,R⁵R^(5a)N—C(═O)-alkyl, R⁵S(═O)-alkoxy, R⁵R^(5a)N—C(═O)-alkoxy,hydroxy-substituted aminoalkoxy, amino-substituted haloalkoxy,hydroxy-substituted haloalkoxy, hydroxy-substituted cyclopropylalkoxy,R⁵S(═O)₂O-substituted cyclopropylalkoxy, heterocyclyl(aminoalkoxy),heteroaryl(hydroxyalkoxy), spiro bicyclyl, spiro heterobicyclyl, spirobicyclyl aliphatic, spiro heterobicyclyl aliphatic, spiro bicycloxy,spiro bicyclylamino, spiro bicycloxoalkoxy, spiro heterobicycloxoalkoxy,spiro bicyclylaminoalkoxy, spiro heterobicyclylaminoalkoxy, spirobicyclyl —C(═O)N—, spiro bicyclyl-C(═O)O—, spiro heterobicyclyl-C(═O)—,spiro heterobicyclyl-C(═O)O—, spiro bicyclylamino-C(═O)N—, spiroheterobicyclylamino-C(═O)N—, spiro bicyclylN-C(═O)NR⁵N—, or spiroheterobicyclyl-C(═O)NR⁵—; or R¹ is

wherein each of X₄ and X₄′ is independently (CR⁴R^(4a))_(m), NR⁵, O, S,S═O or SO₂; each of m and n is independently 0, 1 or 2; and t is 1, 2 or3; R² is H, halo, cyano, hydroxyl, R^(5a)R⁵N—, —C(═O)NR⁵R^(5a),—OC(═O)NR⁵R^(5a), —OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a), —NR⁵C(═O)OR^(5a),—NR⁵C(═O)—R^(5a), R⁵R^(5a)N—O₂S—, R⁵O₂S—, R⁵O₂SR^(5a)N—,R^(5a)R⁵N-alkyl, R⁵(S═O)-alkyl, R⁵R^(5a)N—(C═O)alkyl, R^(5a)R⁵N-alkoxy,R⁵(S═O)-alkoxy, R⁵R^(5a)N—(C═O)-alkoxy, aliphatic, alkoxy,hydroxyalkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy,amino-substituted haloalkoxy, alkylamino haloalkoxy, hydroxy-substitutedhaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy,heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy),carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy,heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy,cycloalkyloxy, (heterocyclo)hydroxyalkoxy, azidoalkoxy, spiro bicyclyl,spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclylaliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino,spiro heterobicyclylamino, spiro bicycloxoalkoxy, spiroheterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spiro bicyclyl —C(═O)—, spirobicyclyl-C(═O)O—, spiro heterobicyclyl-C(═O)—, spiroheterobicyclyl-C(═O)O—, spiro bicyclylamino-C(═O)—, spiroheterobicyclylamino-C(═O)—, spiro bicyclyl-C(═O)NR⁵—, or spiroheterobicyclyl-C(═O)NR⁵—, aryl, heteroaryl, arylaliphatic orheteroarylaliphatic, with the proviso that when alkoxy or alkylamino issubstituted, each of alkoxy or alkylamino is independently substitutedwith one or more hydroxy groups, amino groups or substituted aminogroups; R³ is H, F, Cl, Br, I, —CN, hydroxyl, R^(5a)R⁵N—, aliphatic,alkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl,cycloalkyl aliphatic, cycloalkylalkoxy, or heterocyclylalkoxy; each ofU₁ and U₂ is independently CR⁴ or N; V is NR⁵R^(5a), OR⁵, aliphatic,cycloalkyl, heterocyclyl, aryl, heteroaryl, arylaliphatic, orheteroarylaliphatic; each of W₁, W₂, W₃ and W₄ is independentlyCR⁴R^(4a), NR⁵, CR⁴ or N; X₁ is (CR⁴R^(4a))_(m), NR⁵, O, S, S═O or SO₂,where m is 0, 1 or 2; each of X₂ and X₃ is independently O, S or NR⁵;each of Z₁ and Z₂ is independently NR⁵ or CR⁴R^(4a); each of R⁴ andR^(4a) is independently H, F, Cl, Br, I, —CN, hydroxyl, —NR^(5a)R⁵,alkoxy, cycloalkoxy, heterocycloalkoxy, aliphatic, haloaliphatic,hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic,alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic,cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic,cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl,with the proviso that where R⁴ and R^(4a) are bonded to the same carbonatom, R⁴ and R^(4a), together with the carbon atom they are attached to,optionally form a substituted or unsubstituted 3-8 membered carbocyclicor heterocyclic ring; each of R⁵ and R^(5a) is independently H,R⁶R^(6a)NC(═O)—, R⁶OC(═O)—, R⁶C(═O)—, R⁶R^(6a)NS(═O)—, R⁶OS(═O)N—,R⁶S(═O)—, R⁶R^(6a)NSO₂N—, R⁶OSO₂—, R⁶SO₂—, aliphatic, haloaliphatic,hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic,alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic,cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic,cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl,with the proviso that where R⁵ and R^(5a) are bonded to the samenitrogen atom, R⁵ and R^(5a), together with the nitrogen atom they areattached to, optionally form a substituted or unsubstituted 3-8 memberedring, including spiro and fused bicyclic rings; each of R⁶ and R^(6a) isindependently H, aliphatic, haloaliphatic, hydroxyaliphatic,aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic,alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic,cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic,cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl, orcarbocyclyl; wherein each of R^(5a)R⁵N—, —C(═O)NR⁵R^(5a),—OC(═O)NR⁵R^(5a), —OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a), —NR⁵C(═O)OR^(5a),—NR⁵C(═O)—R^(5a), R⁵R^(5a)N—O₂S—, R⁵O₂S—, R⁵O₂SR^(5a)N—, OR⁵, NR⁵,CR⁴R^(4a), CR⁴, (CR⁴R^(4a))_(m), —NR⁵C(O)—(CR⁴R^(4a))_(p)—,—NR⁵C(═S)—(CR⁴R^(4a))_(p)—, —NR^(5a)—(CR⁴R^(4a))_(p)—,—NR⁵—(CR⁴R^(4a))_(p)C(═O)—, —NR⁵—(CR⁴R^(4a))_(p)C(═S)—, —NR⁵S(O)_(r)—,—NR⁵S(═O)(CR⁴R^(4a))_(p)—, —C(═O)NR⁵—(CR⁴R^(4a))_(p)—,—NR⁵—(CR⁴R^(4a))_(p)—S(═O),_(r)—, R^(5a)R⁵N-alky, R⁵S(═O)-alkyl,R⁵R^(5a)N—C(═O)-alkyl, R^(5a)R⁵N-alkoxy, R⁵S(═O)_(r)-alkoxy,R⁵R^(5a)N—C(═O)—alkoxy, R⁶R^(6a)NC(═O)—, R⁶OC(═O)—, R⁶C(═O)—,R⁶R^(6a)NS(═O)—, R⁶OS(═O)—, R⁶S(═O)—, R⁶R^(6a)NSO₂—, R⁶OSO₂—, R⁶SO₂—,hydroxy-substituted cyclopropylalkoxy, R⁵S(═O)₂O-substitutedcyclopropylalkoxy, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy,hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substitutedhaloalkoxy, alkylamino haloalkoxy, hydroxy-substituted haloalkoxy,alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy,carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy),carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy,heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy,cycloalkyloxy, (heterocyclo)hydroxyalkoxy, azidoalkoxy, spiro bicyclyl,spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclylaliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino,spiro heterobicyclylamino, spiro bicycloxoalkoxy, spiroheterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spiro bicyclyl —C(═O)—, spirobicyclyl-C(═O)O—, spiro heterobicyclyl-C(═O)—, spiroheterobicyclyl-C(═O)O—, spiro bicyclylamino-C(═O)—, spiroheterobicyclylamino-C(═O)—, spiro bicyclyl-C(═O)NR⁵—, or spiroheterobicyclyl-C(═O)NR⁵—, aryl, heteroaryl, arylaliphatic andheteroarylaliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic,alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic,aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic,arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, arylaliphatic, heterocyclylaliphatic,cycloalkylaliphatic, heterocyclyl and carbocyclyl is independentlysubstituted or unsubstituted.
 2. The compound according to claim 1,wherein R³ is independently H, F, Cl, Br, —CN, C₁₋₃ aliphatic, C₁₋₃alkoxy, or C₁₋₃ haloalkyl.
 3. The compound according to claim 1, whereinQ₁ is

wherein Ar is substituted or unsubstituted aryl or heteroaryl; and s is0 or
 1. 4. The compound according to claim 1, wherein Q₂ is


5. The compound according to claim 1, wherein X₁ is O or NR⁵.
 6. Thecompound according to claim 1, wherein Z₁ of formula (IIb) is NH; andthe substructure defined by X₁, U₁ and R³ of Formula I is:


7. The compound according to claim 1, wherein: R¹ is —OC(═O)NR⁵R^(5a),—OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a), —NR⁵C(═O)—R^(5a), R⁵R^(5a)N—O₂S—,R⁵O₂SR^(5a)N—, R⁵S(═O)-alkyl, R⁵R^(5a)NC(═)—C₁₋₆ alkyl, R⁵S(═O)—alkoxy,R⁵R^(5a)NC(═O)-alkoxy, hydroxy-substituted C₁₋₆aminoalkoxy,amino-substituted C₁₋₆ haloalkoxy, hydroxy-substituted C₁₋₆ haloalkoxy,C₄₋₁₀heterocyclyl(aminoC₁₋₆alkoxy), C₁₋₁₀ heteroaryl(hydroxyalkoxy),hydroxy-substituted cyclopropyl C₁₋₆alkoxy, R⁵S(═O)₂O-substitutedcyclopropyl C₁₋₆alkoxy, C₅₋₁₂ spiro bicyclyl, C₅₋₁₂ spiroheterobicyclyl, C₅₋₁₂ spiro bicyclyl C₁₋₆ aliphatic, C₅₋₁₂ spiroheterobicyclyl C₁₋₆ aliphatic, C₅₋₁₂-spiro heterobicycloxo C₁₋₆ alkoxy,C₅₋₁₂ spiro heterobicyclylamino C₁₋₆ alkoxy, C₅₋₁₂ spiro bicyclyl—C(═O)—, C₅₋₁₂ spiro bicyclyl-C(═O)O—, C₅₋₁₂ spiroheterobicyclyl-C(═O)—, C₅₋₁₂ spiro heterobicyclyl-C(═O)O—, C₅₋₁₂ spirobicyelylamino-C(═O)—, C₅₋₁₂ spiro heterobicyclylamino-C(═O)—, C₅₋₁₂spiro bicyclyl-C(═O)NR⁵—, C₅₋₁₂ spiro heterobicyclyl-C(═O)NR⁵—; or R¹ is

wherein each of X₄ and X₄′is independently (CR⁴R^(4a))_(m), NR⁵, O, S,S═O or SO₂; each of m and n is independently 0, 1 or 2; and t is 1, 2 or3; and R² is H, halo, cyano(CN), R^(5a)R⁵N—C₁₋₆ alkoxy, optionallysubstituted C₁₋₆ alkoxy, C₁₋₆ hydroxyalkoxy, C₁₋₆ aminoalkoxy, C₁₋₆hydroxy-substituted aminoalkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino C₁₋₆alkoxy, C₁₋₆ alkoxy C₁₋₆ alkoxy, C₄₋₁₀ heterocyclyloxy C₁₋₆ alkoxy,C₅₋₁₂ spiro bicyclyl, C₅₋₁₂ spiro bicycloxy, C₅₋₁₂ spiro bicyclylamino,C₅₋₁₂ spiro bicycloxo C₁₋₆ alkoxy, C₅₋₁₂ spiro bicyclylamino C₁₋₆alkoxy, C₅₋₁₂ fused heterobicyclyl, C₅₋₁₂ fused heterobicycloxy, C₅₋₁₂fused heterobicyclylamino, C₅₋₁₂ fused heterobicycloxo C₁₋₆ alkoxy,C₅₋₁₂ fused heterobicyclylamino C₁₋₆ alkoxy, C₅₋₁₂ spiro bicyclyl, C₅₋₁₂spiro heterobicyclyl, C₅₋₁₂ spiro bicyclyl C₁₋₆ aliphatic, C₅₋₁₂ spiroheterobicyclyl C₁₋₆ aliphatic, C₅₋₁₂ spiro heterobicycloxo C₁₋₆ alkoxy,C₅₋₁₂ spiro heterobicyclylamino C₁₋₆ alkoxy, C₅₋₁₂ spiro bicyclyl—C(═O)—, C₅₋₁₂ spiro bicyclyl-C(═O)O—, C₅₋₁₂ spiroheterobicyclyl-C(═O)—, C₅₋₁₂ spiro heterobicyclyl-C(═O)O—, C₅₋₁₂ spirobicyclylamino-C(═O)—, C₅₋₁₂ spiro heterobicyclylamino-C(═O)—, C₅₋₁₂spiro bicyclyl-C(═O)NR⁵—, or C₅₋₁₂ spiro heterobicyclyl-C(═O)NR⁵—, C₆₋₁₀aryl, C₁₋₁₀ heteroaryl, C₆₋₁₀ aryl C₁₋₆ aliphatic or C₁₋₁₀ heteroarylC₁₋₆ aliphatic.
 8. The compound according to claim 1, wherein R¹ has oneof the following structures:

wherein each of X₄ and X₄′ is independently (CR⁴R^(4a))_(m), NR⁵, O, S,S═O or SO₂; each of m and n is independently 0, 1 or 2; and t is 1, 2 or3.
 9. The compound of claim 1 having one of the following structures:

or a stereoisomer, a geometric isomer, a tautomer, an N oxide, or apharmaceutically acceptable salt thereof.
 10. The compound of claim 1having one of the following structures:

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide or apharmaceutically acceptable salt thereof.
 11. A compound of Formula V:

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, or apharmaceutically acceptable salt thereof, wherein: Q₂ has Formula (III):

R¹ is —OC(═O)NR⁵R^(5a), —OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a),—NR⁵C(═O)—R^(5a), R⁵R^(5a)N—O₂S—, R⁵O₂S—, R⁵O₂SR^(5a)N—, R⁵S(═O)-alkyl,R⁵R^(5a)N—C(═O)-alkyl, R⁵S(═O)-alkoxy, R⁵R^(5a)N—C(═O)-alkoxy,hydroxy-substituted aminoalkoxy, amino-substituted haloalkoxy,hydroxy-substituted haloalkoxy, heterocyclyl(aminoalkoxy),heteroaryl(hydroxyalkoxy), hydroxy-substituted cyclopropylalkoxy,R⁵S(═O)₂O-substituted cyclopropylalkoxy, spiro bicyclyl, spiroheterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclylaliphatic, spiro bicycloxy, spiro bicyclylamino, spiro bicycloxoalkoxy,spiro heterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spiro bicyclyl-C(═O)—, spirobicyclyl-C(═O)O—, spiro heterobicyclyl-C(═O)—, spiroheterobicyclyl—C(═O)O—, spiro bicyclylamino-C(═O)—, spiroheterobicyclylamino-C(═O)—, spiro bicyclylN—C(═O)NR⁵—, or spiroheterobicyclyl-C(═O)NR⁵—; or R¹ is

wherein each of X₄ and X₄′ is independently (CR⁴R^(4a))_(m), NR⁵, O, S,S═O or SO₂; each of m and n is independently 0, 1 or 2; and t is 1, 2 or3; R² is H, halo, cyano, hydroxyl, R^(5a)R⁵N—, —C(═O)NR⁵R^(5a),—OC(═O)NR⁵R^(5a), —OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a), —NR⁵C(═O)OR^(5a),—NR⁵C(═O)—R^(5a), R⁵R^(5a)N—O₂S—, R⁵O₂S—, R⁵O₂SR^(5a)N—,R^(5a)R⁵N-alkyl, R⁵S(═O)-alkyl, R⁵R^(5a)N—C(═O)-alkyl, R^(5a)R⁵N-alkoxy,R⁵S(═O)-alkoxy, R⁵R^(5a)N—C(═O)-alkoxy, aliphatic, alkoxy,hydroxyalkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy,amino-substituted haloalkoxy, alkylamino haloalkoxy, hydroxy-substitutedhaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy,heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy),carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy,heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy,cycloalkyloxy, (heterocyclo)hydroxyalkoxy, azidoalkoxy, spiro bicyclyl,spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclylaliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino,spiro heterobicyclylamino, spiro bicycloxoalkoxy, spiroheterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spiro bicyclyl-C(═O)—, spirobicyclyl-C(═O)O—, spiro heterobicyclyl-C(═O)—, spiroheterobicyclyl-C(═O)O—, spiro bicyclylamino-C(═O)—, spiroheterobicyclylamino-C(═O)—, spiro bicyclyl—C(═O)NR⁵—, or spiroheterobicyclyl-C(═O)NR⁵—, aryl, heteroaryl, arylaliphatic orheteroarylaliphatic, with the proviso that when alkoxy or alkylamino issubstituted, each of alkoxy or alkylamino is independently substitutedwith one or more hydroxy groups, amino groups or substituted aminogroups; R³ is H, F, Cl, Br, I, —CN, hydroxyl, R^(5a)R⁵N—, aliphatic,alkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl,cycloalkyl aliphatic, cycloalkylalkoxy, or heterocyclylalkoxy; each ofU₁ and U₂ is independently CR⁴ or N; V is NR⁵R^(5a), OR⁵, aliphatic,cycloalkyl, heterocyclyl, aryl, heteroaryl, arylaliphatic, orheteroarylaliphatic; each of W₁, W₂, W₃ and W₄ is independentlyCR⁴R^(4a)NR⁵, CR⁴ or N; X₁ is (CR⁴R^(4a))_(m), NR⁵, O, S, S═O or SO₂,where m is 0, 1 or 2; each of X₂ and X₃ is independently O, S or NR⁵;each of Z₁ and Z₂ is independently NR⁵ or CR⁴R^(4a); each of R⁴ andR^(4a) is independently H, F, Cl, Br, I, —CN, hydroxyl, —NR^(5a)R⁵,alkoxy, cycloalkoxy, heterocycloalkoxy, aliphatic, haloaliphatic,hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic,alkylthioaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic,cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, arylaliphatic, heterocyclylaliphatic,cycloalkylaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl, withthe proviso that where R⁴ and R^(4a) are bonded to the same carbon atom,R⁴ and R^(4a), together with the carbon atom they are attached to,optionally form a substituted or unsubstituted 3-8 membered carbocyclicor heterocyclic ring; each of R⁵ and R^(5a) is independently H,R⁶R^(6a)NC(═O)—, R⁶OC(═O)—, R⁶C(═O)—, R⁶R^(6a)NS(═O)—, R⁶OS(═O)—,R⁶S(═O)—, R⁶R^(6a)NSO₂—, R⁶OSO₂—, R⁶SO₂—, aliphatic, haloaliphatic,hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic,alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic,cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic,cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl,with the proviso that where R⁵ and R^(5a) are bonded to the samenitrogen atom, R⁵ and R^(5a), together with the nitrogen atom they areattached to, optionally form a substituted or unsubstituted 3-8 memberedring, including spiro and fused bicyclic rings; each of R⁶ and R^(6a)isindependently H, aliphatic, haloaliphatic, hydroxyaliphatic,aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic,alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic,cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic,cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl, orcarbocyclyl; wherein each of R^(5a)R⁵N—, —C(═O)NR⁵R^(5a),—OC(═O)NR⁵R^(5a), —OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a), —NR⁵C(═O)OR^(5a),—NR⁵C(═O)—R^(5a), R⁵R^(5a)N—O₂S—, R⁵O₂S—, R⁵O₂SR^(5a)N—, OR⁵, NR⁵,CR⁴R^(4a), CR⁴, (CR⁴R^(4a))_(m), —NR⁵C(O)—(CR⁴R^(4a))_(p)—,—NR⁵C(═S)—(CR⁴R^(4a))_(p)—, —NR^(5a)—(CR⁴R^(4a))_(p)—,—NR⁵—(CR⁴R^(4a))_(p)C(═O)—, —NR⁵—(CR⁴R^(4a))_(p)C(═S)—, —NR⁵S(O)_(r)—,—NR⁵S(═O)(CR⁴R^(4a))_(p)—, —C(═O)NR⁵—(CR⁴R^(4a))_(p)—,—NR⁵—(CR⁴R^(4a))_(p)—S(═O)_(r)—, R^(5a)R⁵N-alkyl, R⁵(S═O)-alkyl,R⁵R^(5a)N—(C═O)-alkyl, R^(5a)R⁵N-alkoxy, R⁵(S═O)-alkoxy,R⁵R^(5a)N—(C═O)-alkoxy, R⁶R^(6a)NC(═O)—, R⁶OC(═O)—, R⁶C(═O)—,R⁶R^(6a)NS(═O)—, R⁶OS(═O)—, R⁶S(═O)—, R⁶R^(6a)NSO₂—, R⁶OSO₂—, R⁶SO₂—,hydroxy-substituted cyclopropylalkoxy, R⁵S(═O)₂O-substitutedcyclopropylalkoxy, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy,hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substitutedhaloalkoxy, alkylamino haloalkoxy, hydroxy-substituted haloalkoxy,alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy,carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy),carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy,heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy,cycloalkyloxy, (heterocyclo)hydroxyalkoxy, azidoalkoxy, spiro bicyclyl,spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclylaliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino,spiro heterobicyclylamino, spiro bicycloxoalkoxy, spiroheterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spiro bicyclyl-C(═O)—, spirobicyclyl-C(═O)O—, spiro heterobicyclyl-C(═O)—, spiroheterobicyclyl-C(═O)O—, spiro bicyclylamino-C(═O)—, spiroheterobicyclylamino-C(═O)—, spiro bicyclyl-C(═O)NR⁵—, or spiroheterobicyclyl-C(═O)NR⁵—, aryl, heteroaryl, arylaliphatic andheteroarylaliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic,alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic,aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic,arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, arylaliphatic, heterocyclylaliphatic,cycloalkylaliphatic, heterocyclyl and carbocyclyl is independentlysubstituted or unsubstituted.
 12. The compound according to claim 11,wherein R³ is independently H, F, Cl, Br, —CN, C₁₋₃ aliphatic, C₁₋₃alkoxy, or C₁₋₃ haloalkyl.
 13. The compound according to claim 11,wherein the substructure defined by Z₁, Z₂, X₂, X₃ and V of Formula (V)is

wherein Ar is substituted or unsubstituted aryl or heteroaryl; and s is0 or
 1. 14. The compound according to claim 11, wherein Q₂ is


15. The compound according to claim 11, wherein X₁ is O or NR⁵.
 16. Thecompound according to claim 11, wherein the substructure defined by X₁,U₁ and R³ is


17. The compound according to claim 11, wherein R¹ is one of thefollowing structures:

wherein each of X₄ and X₄′ is independently (CR⁴R^(4a))_(m), NR⁵, O, S,S═O or SO₂; each of m and n is independently 0, 1 or 2; and t is 1, 2 or3.
 18. The compound of claim 11 having one of the following structures:

or a stereoisomer, a geometric isomer, a tautomer, an N—oxide, or apharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically acceptable carrier, excipient, diluent, adjuvant,vehicle or a combination thereof.
 20. The composition according to claim19 further comprising a therapeutic agent selected from achemotherapeutic agent, an anti-proliferative agent, an agent fortreating atherosclerosis, an agent for treating lung fibrosis, andcombinations thereof.
 21. The composition according to claim 20, whereinthe additional therapeutic agent is adriamycin, rapamycin, temsirolimus,everolimus, ixabepilone, gemcitabin, cyclophosphamide, dexamethasone,etoposide, fluorouracil, imatinib mesylate, dasatinib, nilotinib,erlotinib, lapatinib, iressa, sorafenib, sunitinib, an interferon,carboplatin, topotecan, taxol, vinblastine, vincristine, temozolomide,tositumomab (Bexxar), trabedectin, Avastin (bevacizumab), Herceptin(trastuzumab), Erbitux (cetuximab), Vectibix (panitumumab), or acombination thereof.
 22. A compound of Formula (I):

or a stereoisomer, a geometric isomer, a tautomer, an N—oxide, or apharmaceutically acceptable salt thereof, wherein: Q₁ is formula (IIb):

Q₂ is formula (III):

R¹ is:

wherein each of X₄ and X₄′ is independently (CR⁴R^(4a))_(m), NR⁵, O, S,S═O or SO₂; each of m and n is independently 0, 1 or 2; and t is 1, 2 or3; R² is H, halo, cyano, hydroxyl, R^(5a)R⁵N—, —C(═O)NR⁵R^(5a),—OC(═O)NR⁵R^(5a), —OC(═O)OR⁵, —NR⁵C(═O)NR⁵R^(5a), —NR⁵C(═O)OR^(5a),—NR⁵C(═O)—R^(5a), R⁵R^(5a)N—O₂S—, R⁵O₂S—, R⁵O₂SR^(5a)N—,R^(5a)R⁵N-alkyl, R⁵(S═O)-alkyl, R⁵R^(5a)N—(C═O)alkyl, R^(5a)R⁵N-alkoxy,R⁵(S═O)-alkoxy, R⁵R^(5a)N—(C═O)-alkoxy, aliphatic, alkoxy,hydroxyalkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy,amino-substituted haloalkoxy, alkylamino haloalkoxy, hydroxy-substitutedhaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy,heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy),carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy,heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy,cycloalkyloxy, (heterocyclo)hydroxyalkoxy, azidoalkoxy, with the provisothat when alkoxy or alkylamino is substituted, each of alkoxy oralkylamino is independently substituted with one or more hydroxy groups,amino groups or substituted amino groups; R³ is H, F, Cl, Br, I, —CN,hydroxyl, R^(5a)R⁵N—, or aliphatic; each of U₁ and U₂ is independentlyCR⁴ or N; V is NR⁵R^(5a), OR⁵, aliphatic, cycloalkyl, heterocyclyl,aryl, heteroaryl, arylaliphatic, or heteroarylaliphatic; each of W₁, W₂,W₃ and W₄ is independently CR⁴ or N; each of X₁, X₂ and X₃ isindependently O; each of Z₁ and Z₂ is independently NR⁵ or CR⁴R^(4a);each of R⁴ and R^(4a) is independently H, F, Cl, Br, I, —CN, hydroxyl,—NR^(5a)R⁵, alkoxy, cycloalkoxy or aliphatic, with the proviso thatwhere R⁴ and R^(4a) are bonded to the same carbon atom, R⁴ and R^(4a),together with the carbon atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered carbocyclic or heterocyclicring; each of R⁵ and R^(5a) is independently H, aliphatic, aryl,heteroaryl, heterocyclyl or carbocyclyl, with the proviso that where R⁵and R^(5a) are bonded to the same nitrogen atom, R⁵ and R^(5a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, including spiro andfused bicyclic rings; each of R⁶ and R^(6a) is independently H,aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic,alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic,heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic,heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic,heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl,heterocyclyl, or carbocyclyl; wherein each of hydroxy-substitutedcyclopropylalkoxy, R⁵S(═O)₂O-substituted cyclopropylalkoxy, aliphatic,alkoxy, hydroxyalkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy,haloalkoxy, amino-substituted haloalkoxy, alkylamino haloalkoxy,hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxyalkoxy,arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy,heterocyclyl(hydroxyalkoxy), carbocyclyl(hydroxyalkoxy),aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy,carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy,(heterocyclo)hydroxyalkoxy, azidoalkoxy, aryl, heteroaryl, arylaliphaticand heteroarylaliphatic, haloaliphatic, hydroxyaliphatic,aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic,alkylthioaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic,cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, arylaliphatic, heterocyclylaliphatic,cycloalkylaliphatic, heterocyclyl and carbocyclyl is independentlysubstituted or unsubstituted.
 23. The compound according to claim 1,wherein: the substructure defined by X₁, U₁ and R³ of Formula (I) is

Q₁ is

 wherein Ar is substituted or unsubstituted aryl; Q₂ iS

R¹ is

 wherein each of X₄ and X₄′ is O, R^(5a) is H, and t is 3; and R² is H.